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  5. 中国及全球抑郁症流行病学特征与致病因素综合分析

中国及全球抑郁症流行病学特征与致病因素综合分析

深度研究匿名用户发表于 2025年11月24日 14:152阅读
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1. 全球及中国抑郁症流行病学特征与致病因素综合分析

1.1 全球抑郁症发病率的总体特征

抑郁症作为全球主要的公共卫生挑战，其流行病学特征在过去三十年间发生了显著变化。根据2021年全球疾病负担研究（GBD2021）的数据，从1990年至2021年，全球抑郁症的现患病例数和伤残调整寿命年（DALY）均增加了超过1.8倍1。尽管如此，全球年龄标准化患病率（ASPR）和年龄标准化DALY率（ASDR）在1990年至2019年间略有下降，其中ASPR下降了1.32%，ASDR下降了1.84%1。这种下降主要发生在2005年至2010年，贡献主要来自中低社会人口学指数（SDI）和低SDI地区1。

然而，2019年至2021年间，全球抑郁症的ASPR和ASDR出现了惊人的跳跃式增长，ASPR增加了近11%，ASDR增加了13%1。这一显著增长尤其在高SDI地区表现突出1。

从地区分布来看，2021年低SDI地区表现出最高的年龄标准化发病率、患病率和DALY率，而中SDI地区这些指标的增长速度最快2。具体到地理区域，中非和东部撒哈拉以南非洲在2021年拥有最高的年龄标准化发病率、患病率和DALY率2。国家层面，乌干达在2021年的所有年龄标准化率中排名最高2。

年龄和性别分布方面，抑郁症在不同年龄段和性别之间存在差异。女性在全球范围内，尤其是在许多精神疾病（如焦虑、抑郁、疲劳、精神病性症状）的患病率和严重程度方面均高于男性3。在抑郁症中，女性的患病率比男性高出约1.56倍（OR=1.56）3。然而，1990年至2019年间，女性的ASPR和ASDR有所下降，而男性则有所增加，但2019年后这一趋势逆转1。

特殊年龄群体中，儿童和青少年抑郁症或抑郁症状的全球汇总患病率约为21.3%（轻中度至重度）4。这一比例在1989年至2022年间呈上升趋势4。在10-24岁的青少年和年轻人中，主要抑郁症的负担也在显著增加，全球患病率上升了56.36%，其中东部撒哈拉以南非洲的增幅最大（184.26%）5。老年人群（60岁及以上）的抑郁症患病率也较高，全球汇总患病率为19.2%6，且随着年龄的增长，这种疾病的发生率和DALY率也在增加7。低SDI地区的老年抑郁症负担最为显著，而中SDI地区的增长速度最快2。

2020年后COVID-19大流行的影响尤为突出。疫情导致抑郁症和焦虑症的额外病例大幅增加。据估计，2020年全球新增了5320万例重度抑郁症病例，使总患病率增加了27.6%8。年轻人和女性受疫情影响更严重，其抑郁症和焦虑症的患病率增加幅度更大8。对儿童和青少年的研究显示，疫情期间临床上显著的抑郁症状和焦虑症状的汇总患病率分别为25.2%和20.5%9。这些数字是疫情前的两倍，并且随着疫情的深入而增加，尤其是在年龄较大的儿童和女孩中更为明显9。大学生的抑郁症状和焦虑症状患病率在COVID-19爆发后也有所上升，分别为35.9%和40.7%10。

1.2 中国抑郁症流行病学的独特性

中国的抑郁症流行病学呈现出与全球总体趋势既有相似之处又具独特性的特征。与全球年龄标准化患病率（ASPR）和伤残调整寿命年率（ASDR）在2019年前的下降趋势一致，中国在某些时期也观察到类似现象。然而，中国抑郁症的整体患病率，特别是诊断率和治疗率，在全球范围内处于较低水平。例如，一项2012-2015年对中国成年人的调查显示，任何抑郁症的12个月患病率为2.1%，终生患病率为3.3% 11。尽管这一数字相对较低，但其造成的疾病负担仍然巨大，抑郁症被估计为中国导致伤残调整生命年损失的第二大原因 11。

年龄分布特征：

在中国，抑郁症的年龄分布存在显著特点。老年群体（60岁及以上）是抑郁症的高发人群。在中国中老年人中，抑郁症状的患病率较高，且与全因死亡率及心血管疾病死亡率的风险增加相关 1213。在对中国健康与养老追踪调查（CHARLS）数据的分析中，45岁及以上人群中，男性的抑郁率达到26.67%，女性更是高达38.37% 14。农村地区独居老年人的抑郁风险尤为突出，自我健康评价差、疼痛、虚弱、夜间睡眠时间短、睡眠质量差、生活满意度低和探视频率低等因素与抑郁症状独立相关 15。患有慢性疾病的老年人抑郁症患病率更高，一项基于CHARLS数据的研究发现，慢性病老年人抑郁症患病率为19.2% 16。

与老年群体高发相对，青少年抑郁症在发达地区的患病率也日益突出。例如，在江苏省南京市，一项针对13-18岁青少年的研究显示，城市地区的青少年抑郁症风险更高 17。青少年抑郁症的患病率持续上升，对其认知、情感和行为发展产生负面影响 17。

性别差异：

中国的抑郁症流行病学数据也普遍显示出女性患病率高于男性的特点，这与全球趋势一致。 lifetime患病率和12个月患病率女性均高于男性，比值比（OR）分别为1.44（95% CI 1.20-1.72）和1.41（95% CI 1.12-1.78） 11。在针对大学生群体的研究中，女性在焦虑方面的得分显著高于男性，且有更高比例的女性大学生出现超出正常阈值的焦虑症状。尽管在抑郁和压力水平上，男女大学生平均分无显著差异，但有更高比例的男性大学生表现出不同程度的抑郁 18。此外，研究发现，肥胖与抑郁症发病的关系在男性中更为显著，而体重状况（无论是体重不足还是超重）与抑郁症状之间的关系在女性和男性中均呈负相关 14。

城乡/地区差异：

城乡差异是中国抑郁症流行病学的一个重要维度。一项关于老年人抑郁症的系统回顾和Meta分析发现，在发展中国家（包括中国），城乡居住与老年人抑郁症之间的关联不显著（OR=0.91, 95% CI=0.46, 1.77） 19。然而，具体到中国内部的研究则显示出更细致的差异。例如，一项针对中国农村和城市残疾老年人抑郁症预测因素的研究发现，农村残疾老年人的抑郁率（57.67%）高于城市残疾老年人（44.59%） 20。另一方面，城市化进程也带来新的挑战。例如，在江苏省的青少年群体中，居住在城市地区是青少年抑郁症的风险因素，其优势比（AOR）为3.324（95% CI: 1.077-10.267） 17。这可能与城市生活带来的压力、竞争以及社会生态环境的复杂性有关。

此外，不同地区之间的经济发展水平和社会文化因素也可能影响抑郁症的分布。例如，一项关于痴呆症风险因素的横断面研究显示，中国城乡地区痴呆症的患病率及其风险因素存在显著差异，提示需要针对城乡居民制定不同的预防策略 21。在迁移人口中，农村到城市迁移并定居在城市地区的个体在晚年期的抑郁水平低于返回农村地区的“回流移民”或农村非移民，这表明城市化和居住地的选择对心理健康具有长期影响，且性别在这一过程中扮演着重要角色 22。

1.3 特殊人群发病率的聚焦

抑郁症在特定人群中表现出更高的发病率和独特的风险因素，这些人群往往面临特殊的生理、心理和社会挑战。深入探讨这些特殊人群的抑郁症流行病学特征，对于精准干预和政策制定至关重要。

青少年群体（18岁以下）：
全球范围内，青少年抑郁症的患病率呈上升趋势。一项涵盖1990年至2019年的全球疾病负担研究发现，10-24岁青少年和年轻人的抑郁症患病率、发病率和伤残调整寿命年（DALY）均有所增加 23。特别是在高收入北美和澳大拉西亚等高收入地区，年龄标准化患病率和发病率呈上升趋势 23。中国青少年群体的抑郁症问题同样突出。根据中国一项大规模精神障碍调查，6-16岁儿童和青少年的任何精神障碍加权患病率为17.5% 24。其中，男性、年龄较小的个体以及来自发达地区的儿童和青少年患任何精神障碍的患病率更高 24。值得注意的是，男性群体中任何精神障碍的患病率随年龄增长而降低，而女性群体则随年龄增长而升高 24。此外，青少年抑郁症与成年期自杀行为之间存在显著关联，一项Meta分析指出，青少年时期有抑郁史的人在成年期出现自杀行为的可能性更高（OR = 3.97, 95% Cl: 2.79, 5.63） 25。

围产期女性：
围产期（包括孕期和产后）是女性发生抑郁症的高风险阶段。全球范围内，围产期抑郁症的平均总患病率为26.3%，其中产前抑郁症为28.5%，产后抑郁症为27.6% 26。使用自我报告量表的研究所报告的患病率（27.4%）显著高于使用结构化访谈的研究所报告的患病率（17.0%） 26。发展中国家，特别是中国，产后抑郁症的患病率较高 27。一项系统评价和Meta分析显示，产后抑郁症的汇总患病率为14.0%（95%CI, 12.0%-15.0%），且各国患病率差异较大（从5.0%到26.32%） 27。中国女性在围产期的抑郁风险受多种因素影响，包括妊娠期糖尿病（GDM）、孕期抑郁史、有抑郁症病史、分娩男孩以及分娩时硬膜外麻醉等 27。孕前精神健康问题对婴儿的情绪反应性有独立预测作用，即使在调整了围产期暴露后，孕前风险仍有88%是直接效应 28。研究发现，妊娠期糖尿病和围产期抑郁之间存在双向关系，尤其在孕前体重正常的女性中，孕期抑郁症状可以预测随后的妊娠期糖尿病诊断，而妊娠期糖尿病诊断则可以预测随后的产后抑郁症状 29。这些发现强调了围产期女性心理健康筛查和干预的重要性。

老年群体（60岁以上）：
随着全球人口老龄化加速，老年抑郁症日益成为一个严峻的公共卫生问题。全球汇总患病率约为19.2%，且随着年龄增长，疾病的发生率和DALY率也在增加。低SDI地区的老年抑郁症负担最为显著，而中SDI地区的增长速度最快。老年抑郁症状与心血管疾病风险增加密切相关 30。一项对CHARLS数据库的分析发现，在2年的随访中，5845名60岁及以上老年人中有31.17%发展为抑郁症 31。年龄、性别、慢性病数量、疼痛区域数量、生活满意度和如厕距离等因素均与老年抑郁症显著相关 31。例如，虚弱（Frailty）显著增加心血管疾病风险，而抑郁症状部分介导了这种关系 30。从虚弱状态的转变（进入虚弱或虚弱状况改善）也与心血管疾病风险的变化相关 30。这些结果强调了在老龄化人口中，针对虚弱和抑郁症状进行综合干预以预防心血管疾病的必要性 30。此外，孤独感、社会隔离以及与年龄相关的生理和社会变化（如丧偶、退休、慢性疾病）都可能增加老年人患抑郁症的风险。

2. 生物医学致病机制：从分子到系统的多维度解析

2.1 遗传与表观遗传基础

抑郁症的发生发展被认为是遗传与环境因素复杂交互作用的结果。近年来，生物医学研究在阐明其分子和系统层面的致病机制方面取得了显著进展，其中遗传易感性和表观遗传调控扮演了关键角色。

遗传易感性

遗传因素对抑郁症的风险贡献约为30-40% 3233。全基因组关联研究（GWAS）是识别抑郁症遗传变异的主要方法。迄今为止，大规模的GWAS研究已经识别出数百个与抑郁症相关的基因座，这些研究通常涉及数十万甚至数百万的抑郁症患者和对照组 343536。

一项涵盖29个国家688,808名重度抑郁症（MD）患者和4,364,225名对照组的多族裔全基因组关联研究（GWAS）元分析，发现了635个基因座上的697个关联，其中293个是新发现的 34。通过精细定位和功能分析，研究人员识别出308个高可信度基因关联，并发现其在突触后密度和受体簇中存在富集。神经细胞类型富集分析表明，兴奋性神经元、抑制性神经元和中型多棘神经元以及杏仁核神经元均与抑郁症相关 34。另一项针对130万人的抑郁症GWAS元分析确定了243个风险基因座，其中64个是新的，包括编码谷氨酸和GABA受体的基因，这些受体是抗抑郁药物的靶点 36。这些研究还强调了前额叶脑区在抑郁症中的重要性 35。

多基因风险评分（PRS）作为一种工具，能够量化个体基于大量常见遗传变异的抑郁症遗传倾向。PRS-CS等方法利用全基因组关联汇总统计数据和外部连锁不平衡（LD）参考面板来推断单核苷酸多态性（SNP）的后验效应大小，并在预测人类复杂性状和疾病方面显示出潜力 37。研究表明，在欧洲或多族裔数据上训练的多基因评分能够预测所有族裔的MD状态，解释了欧洲人MD责任方差的5.8% 34。高多基因负担的抑郁症患者复发率和精神共病风险显著增加，且存在显著的性别差异 36。

遗传学研究还发现，抑郁症与其他精神疾病（如焦虑症、精神分裂症和双相情感障碍）和神经质存在遗传重叠 363839。例如，焦虑障碍与抑郁症的共病率高达50%，提示两者可能共享部分遗传和病理机制。

表观遗传调控

表观遗传学是指不涉及DNA序列改变但影响基因表达和翻译的过程，主要包括DNA甲基化、组蛋白修饰和微RNA（miRNAs）等 4041。表观遗传机制被认为是连接环境暴露（如压力）与基因表达之间的重要桥梁，并能够介导不良生活事件对抑郁症风险的持久影响 324042。

  1. DNA甲基化 (DNAm)：DNA甲基化通常发生在CpG位点，通过添加甲基基团来抑制基因表达。研究表明，压力相关的DNA甲基化改变与抑郁症相关 42。例如，糖皮质激素受体基因（NR3C1）的DNA甲基化改变与抑郁症、童年期压力、低社会经济地位和慢性疼痛有关 4243。血清素转运体基因（SLC6A4）和脑源性神经营养因子（BDNF）等神经递质和神经营养因子相关基因的甲基化异常也被认为是抑郁症的潜在治疗靶点 42。环境危害因素的联合暴露，如挥发性有机化合物（VOCs），可以导致表观遗传改变，例如长非编码RNA MALAT1的显著减少以及八个基因的显著下调，这些改变可能导致突触密度、树突数量和密度的异常，进而损害运动学习或空间记忆 44。

  2. 组蛋白修饰：组蛋白修饰通过改变染色质结构来调节基因的可及性，从而影响基因转录。组蛋白乙酰化、甲基化、磷酸化和泛素化等多种修饰方式均可能参与抑郁症的病理生理过程 324041。研究发现，组蛋白血清素化（histone serotonylation，即H3K4me3Q5ser）在背缝核（DRN）中调节应激和抗抑郁药物介导的基因表达和行为发挥重要作用 45。慢性应激小鼠的DRN中H3K4me3Q5ser动态失调，而抗抑郁药物和病毒介导的干预可以减弱应激介导的基因表达和行为改变 45。此外，组蛋白H3赖氨酸27单甲基化（H3K27me1）被发现与应激易感性相关，早期生活应激（ELS）或慢性社交失败应激（CSDS）易感小鼠在伏隔核（NAc）中H3K27me1富集增加，这在控制神经元兴奋性的基因中尤其明显，并可导致社交、情绪和认知异常 46。这些发现提示组蛋白修饰可能成为抑郁症治疗的新靶点。

  3. 微RNA (miRNAs)：miRNAs是非编码RNA分子，通过结合mRNA来调节基因表达。虽然在此次提供的参考文献中未直接详细提及miRNAs在抑郁症中的具体作用，但其作为表观遗传调控的一部分，也被广泛认为是介导环境与基因交互作用、影响神经可塑性和情绪调节的重要机制。

总而言之，遗传易感性通过多基因作用增加了抑郁症的风险，而表观遗传机制则为环境因素如何在不改变DNA序列的情况下，持久地影响基因表达和个体对压力的反应提供了分子基础。这些发现为理解抑郁症的复杂病因提供了新的视角，并为开发新的诊断生物标志物和治疗策略指明了方向。

2.2 神经代谢与肠道微生物-脑轴

抑郁症的生物学机制日益被认为是多系统失调的结果，其中神经代谢异常和肠道微生物-脑轴（Gut-Brain Axis）的紊乱扮演着核心角色。代谢组学研究为我们揭示了能量代谢和脂代谢在抑郁症发生发展中的关键作用，同时，肠道菌群通过其代谢产物对神经递质系统的影响也受到了广泛关注。

能量代谢异常

抑郁症患者常伴有全身和局部葡萄糖代谢障碍，这贯穿于疾病的整个病程，影响葡萄糖摄取、糖蛋白转运、糖酵解、三羧酸循环（TCA）和氧化磷酸化（OXPHOS）等多个过程 47。

  1. 三羧酸循环（TCA）与氧化磷酸化： TCA循环是细胞产生能量的关键途径。研究发现，在慢性社会挫败应激（CSDS）小鼠模型和首发抑郁症患者中，TCA循环受到抑制，这与线粒体氧化磷酸化功能受损同时发生 48。TCA循环关键酶的活性失调，如丙酮酸脱氢酶（PDH）活性受抑制，是导致线粒体TCA通量减少的重要原因。糖皮质激素受体（GR）通过刺激丙酮酸脱氢酶激酶2（PDK2）的表达，进而增强PDH磷酸化，抑制其活性，最终导致脑能量代谢受损 48。此外，线粒体功能障碍在双相情感障碍（BD）患者中也得到证实，尽管在药物初治的重度抑郁发作期BD患者中，TCA循环酶（柠檬酸合酶、苹果酸脱氢酶、琥珀酸脱氢酶）的活性未见显著改变 49。然而，脑能量缺陷被认为是偏头痛中氧化应激的来源，且三羧酸循环中的异柠檬酸脱氢酶等酶与NADPH的产生密切相关，NADPH是神经元抗氧化防御的重要组成部分 50。
  2. 葡萄糖代谢与胰岛素抵抗： 抑郁症患者的葡萄糖代谢障碍可能源于胰岛素抵抗、高血糖诱导的损伤、氧化应激、星形胶质细胞异常和线粒体功能障碍。这些机制导致能量供应不足，影响突触可塑性，引起神经元死亡，并对奖赏网络造成功能和结构损害 47。糖尿病患者患抑郁症的风险是普通人群的2-3倍 5152，反之，抑郁症也会增加2型糖尿病的发生风险，并加重高血糖、胰岛素抵抗以及微血管和大血管并发症 5354。这种双向关联反映了共同的病理生理机制，包括自主神经和神经内分泌失调、体重增加、炎症以及海马结构改变 53。

脂代谢异常

脂代谢在抑郁症中也表现出紊乱。血浆脂蛋白水平的变化、鞘脂代谢以及磷脂代谢的异常都与抑郁症相关。

  1. 鞘脂代谢： 鞘脂是细胞膜的重要组成部分，并在细胞信号传导中发挥作用 55。研究发现，在慢性不可预测轻度应激（CUMS）模型中，载脂蛋白E（APOE）小鼠表现出更严重的抑郁样行为和皮质鞘脂代谢失调。特定抗抑郁药物可以通过调节鞘磷脂酶（AMSase）来缓解神经酰胺（Cer）和鞘磷磷脂（SM）之间的不平衡，从而改善抑郁行为 56。此外，鞘氨醇-1-磷酸（S1P）是一种生物活性脂质介质，通过激活S1P受体2（S1PR2）参与肝脏脂质代谢的调节 57。鞘脂代谢的紊乱可能通过影响神经元膜功能和信号通路，进而影响情绪调节。
  2. 甘油磷脂（GP）与脂肪酸（FA）代谢： 多组学数据显示，抑郁症小鼠肠道菌群失调导致甘油磷脂代谢紊乱 58。粪便样本中的差异脂质代谢物主要属于甘油磷脂和脂肪酸代谢，其中“FA/GP-厚壁菌门（Firmicutes）”、“FA/GP-Akkermansia”和“FA/GP-双歧杆菌”是重要的代谢物-细菌类群相关对 58。血清和海马样本中的差异脂质代谢物也主要映射到甘油磷脂代谢。这些发现提示肠道菌群可能通过影响外周/中枢甘油磷脂代谢，在抑郁症小鼠的抑郁样行为发生中发挥关键作用 58。

肠道微生物-脑轴（Gut-Brain Axis）

肠道微生物群落及其代谢产物通过复杂的肠道-脑轴与抑郁症的发生发展密切相关 596061。肠道菌群失调（dysbiosis）被认为是抑郁症发病机制和进展的重要因素 59。

  1. 微生物多样性与菌群组成： 抑郁症患者的肠道菌群组成和功能（例如代谢物）发生改变 59。系统综述发现，焦虑症和抑郁症可能与促炎性菌种（如肠杆菌科和脱硫弧菌属）丰度较高以及产生短链脂肪酸（SCFAs）的细菌（如粪杆菌属）丰度较低有关 62。在酒精戒断小鼠模型中，焦虑和抑郁样行为与血清素（5-HT）代谢紊乱和肠道菌群失调相关，表现为粪杆菌属和罗氏菌属等产生SCFAs的细菌减少 63。
  2. 短链脂肪酸（SCFAs）： SCFAs是肠道菌群发酵膳食纤维的产物，对宿主健康至关重要。抑郁症小鼠模型中，SCFAs水平显著改变，并与大部分差异菌属显著相关 58。脑部SCFAs被证实可以通过激活乙酰辅酶A合成酶短链家族成员2（ACSS2），并通过PPARγ-TPH2轴改善抑郁样行为 64。ACSS2是快速和持久抗抑郁反应的新靶点。D-甘露糖作为一种天然存在的己糖，能显著逆转慢性束缚应激小鼠的肠道菌群失调，增加脑部SCFAs，并通过ACSS2-PPARγ-TPH2轴抵抗抑郁样行为 64。
  3. 色氨酸代谢产物与神经递质： 肠道菌群通过影响色氨酸代谢，进而调节神经递质5-羟色胺（5-HT）的合成和功能。在抑郁症小鼠模型中，海马样本中色氨酸途径的四种差异神经递质发生改变 58。益生元菊粉（inulin）可以通过增加粪杆菌属和罗氏菌属的丰度，促进SCFAs的产生，并调节5-HT代谢，从而改善酒精戒断小鼠的焦虑和抑郁样行为，表现为5-HT和5-羟色氨酸（5-HTP）水平升高，以及结肠色氨酸羟化酶1（TPH1）表达上调 63。迷走神经被认为是肠道-脑轴中的关键通路，有研究指出迷走神经切断术可以阻断粪菌移植引起的抑郁样表型，提示迷走神经在肠道菌群影响抑郁症中的作用 60。

综上所述，神经代谢和肠道微生物-脑轴在抑郁症的病理生理学中发挥着复杂而关键的作用。能量代谢的紊乱，尤其是TCA循环和氧化磷酸化障碍，以及脂代谢中鞘脂和甘油磷脂的异常，都为抑郁症的发生提供了生物学基础。同时，肠道菌群通过其代谢产物，尤其是SCFAs和色氨酸衍生物，直接或间接影响神经递质的平衡和脑功能，为抑郁症的治疗提供了新的靶点和干预策略。

2.3 炎症与神经免疫失衡

炎症反应和神经免疫失衡在抑郁症的发生发展中扮演着关键角色，越来越多的证据表明抑郁症不仅仅是一种纯粹的神经系统疾病，更是一种神经免疫疾病 6566。系统性炎症与抑郁症之间的关联性已被广泛证实，其通过多种机制影响大脑功能和情绪调节。

炎症标记物的异常表达

抑郁症患者常表现出外周炎症生物标志物的升高，这包括C反应蛋白（CRP）、白细胞以及多种促炎细胞因子 6567。

  1. C反应蛋白（CRP）： CRP是炎症反应的经典生物标志物。多项研究和荟萃分析表明，抑郁症患者血清或血浆中的CRP水平升高 6568。CRP水平越高，抑郁症状的严重程度通常也越高，并可能预示着对治疗的反应较差 68。大约三分之一的抑郁症患者表现出低度炎症状态（CRP水平在1-3 mg/L或更高），这提示抑郁症可能存在一个具有独特病因学、临床病程和治疗反应的亚组，被称为“炎症型抑郁症” 666869。然而，也有研究发现，尽管血浆中炎症蛋白（如IL-6、IL-7、IL-8、IL-10、IL-12/IL-23p40、IL-16、IL-17A、IFN-γ和TNF-α）的水平在不同CRP水平的抑郁症患者之间存在差异，但免疫相关基因的表达水平在很大程度上独立于CRP水平 70。这表明CRP虽然是重要的炎症指标，但可能无法完全捕捉抑郁症中免疫相关的全部变化，提示还存在其他生物学机制将基因表达信号转化为蛋白质和细胞水平的炎症。
  2. 白细胞与细胞因子： 抑郁症患者通常也表现出白细胞计数、中性粒细胞计数的升高，以及多种促炎细胞因子（如肿瘤坏死因子-α [TNF-α]、白介素-1β [IL-1β]、白介素-6 [IL-6]）水平的异常 6769。这些升高的细胞因子可以通过多种途径进入大脑，并与几乎所有已知参与抑郁症病理生理学的领域相互作用，包括神经递质代谢、神经内分泌功能和神经可塑性 67。例如，在对重度抑郁症（MDD）患者的转录组学分析中发现，免疫代谢通路在CRP > 1 mg/L的个体中被激活 71。

神经炎症对大脑功能的损害机制

外周炎症信号可以穿过血脑屏障，激活中枢神经系统中的免疫细胞，特别是小胶质细胞，从而引发神经炎症 6567。神经炎症被认为是导致抑郁症核心症状的关键机制之一。

  1. 小胶质细胞活化： 小胶质细胞是大脑中的主要免疫细胞，在神经炎症中扮演着重要角色。当小胶质细胞被激活时，它们会释放大量的促炎细胞因子和趋化因子，对神经元产生毒性作用，并影响突触功能和神经发生 6572。小胶质细胞的M1/M2极化失衡与抑郁症的发生密切相关 73。M1型小胶质细胞被认为是促炎性的，而M2型则具有抗炎和神经保护作用。在慢性应激状态下，小胶质细胞向M1型极化增加，导致促炎细胞因子释放增加，进而损害海马神经发生和前额叶皮层功能 7374。例如，星形胶质细胞激活的小胶质细胞可以引起负性情绪状态，表现为快感缺乏和厌恶感 72。这种负性情绪状态的产生，部分是通过白介素-6信号通路和环氧合酶-1介导的微胶质细胞内前列腺素合成，导致纹状体神经元兴奋性降低而实现 72。此外，神经元分泌的含有miR-9-5p的外泌体可以促进小胶质细胞的M1极化，释放促炎细胞因子，加剧神经损伤，miR-9-5p已被发现与重度抑郁症患者血清外泌体中的miR-9-5p表达水平显著升高相关 75。
  2. 细胞因子风暴与神经递质、神经可塑性： 促炎细胞因子不仅直接损伤神经元，还会影响神经递质系统。例如，它们可以改变色氨酸代谢途径，增加犬尿氨酸向犬尿酸的转化，减少5-羟色胺的合成，从而影响情绪调节 67。此外，神经炎症还会损害海马区和前额叶皮层的神经可塑性，包括树突棘密度、突触连接和神经发生，这些区域的功能障碍与抑郁症的认知和情感症状密切相关 67。应激诱导的STING-TBK1-IRF3信号通路的激活与神经炎症和抑郁样行为有关，通过激活STING通路可以抑制神经炎症并增强小胶质细胞的吞噬作用，从而改善慢性应激引起的抑郁样行为 76。
  3. 内分泌与免疫的相互作用： 抑郁症还会影响免疫系统对病毒感染的反应。重度抑郁症患者外周血单核细胞（PBMCs）和巨噬细胞中，Abelson辅助整合位点1（AHI1）的表达降低，导致抗病毒先天免疫反应减弱，使得抑郁症患者对病毒感染的易感性更高 77。研究发现，抑郁症相关的精氨酸加压素（AVP）会诱导巨噬细胞中AHI1的减少，AHI1是I型干扰素（IFN-I）信号的关键稳定剂，通过招募OTUD1去泛素化并稳定Tyk2来发挥作用 77。AHI1的减少会下调Tyk2和IFN-I信号活性，从而损害抗病毒免疫功能。

慢性疼痛共病时的炎症叠加效应

抑郁症与慢性疼痛之间存在高度共病性，据估计高达80%的慢性疼痛患者同时患有抑郁症，反之亦然 7879。这种共病性不仅增加了患者的痛苦和治疗难度，也使得疾病负担更为沉重。神经炎症被认为是连接疼痛和抑郁共病的关键机制之一 7879。

  1. 共同的病理生理核心： 疼痛和抑郁共享许多病理生理机制，包括炎症反应。炎症相关基因的多态性可导致对抑郁表现的易感性，并可能改变抗抑郁治疗的反应 78。慢性炎症可能是抑郁症及其常见共病（包括心血管代谢疾病、自身免疫性疾病和慢性疼痛）之间双向共病率高的原因 69。
  2. 炎症介质的双向作用： 在慢性疼痛状态下，持续的炎症反应会导致促炎细胞因子在全身和中枢神经系统中的升高。这些细胞因子可以加剧神经炎症，影响神经递质平衡和神经可塑性，从而诱发或加重抑郁症状 79。反之，抑郁症本身也能促进慢性疼痛的发展或恶化，例如通过增强对疼痛的敏感性或降低疼痛阈值。例如，类风湿关节炎（RA）是一种以炎症为特征的慢性自身免疫性疾病，其患者出现精神疾病共病的风险很高，其中重度抑郁症是最常见的共病，患病率高达41.0% 80。这进一步印证了炎症在疼痛与抑郁共病中的核心作用。

综上所述，炎症与神经免疫失衡是抑郁症发病机制中不可忽视的重要环节。从外周炎症标志物的升高，到中枢神经系统中小胶质细胞的激活和细胞因子风暴，再到对神经递质、神经可塑性和抗病毒免疫功能的损害，炎症以多层次、多途径的方式参与抑郁症的发生发展。尤其是在与慢性疼痛等疾病共病时，炎症的叠加效应使得病理过程更为复杂。深入理解这些机制，将有助于开发针对炎症通路的靶向治疗策略，为抑郁症的精准医学提供新的方向。

2.4 神经内分泌异常

神经内分泌系统在抑郁症的发生发展中扮演着核心角色，特别是下丘脑-垂体-肾上腺（HPA）轴的功能失调，是抑郁症最重要的生物学标志之一，影响着情绪调节和应激反应 818283。

HPA轴功能失调与抑郁症

HPA轴是一个复杂的神经内分泌系统，负责调节身体对压力的反应。其主要成分包括下丘脑释放的促肾上腺皮质激素释放激素（CRH），垂体分泌的促肾上腺皮质激素（ACTH），以及肾上腺产生的皮质醇。正常情况下，HPA轴在压力下被激活，皮质醇水平升高，以帮助身体应对挑战；当压力解除后，通过负反馈机制，皮质醇水平回落。

然而，在抑郁症患者中，HPA轴常表现出过度活跃和功能失调 83。

  1. 皮质醇节律紊乱： 正常情况下，皮质醇的分泌呈现昼夜节律，清晨达到高峰，夜间降至低谷 8485。抑郁症患者往往表现出皮质醇节律紊乱，例如夜间皮质醇水平升高，或者皮质醇分泌曲线扁平化，即昼夜峰谷差异不明显 84。这种异常的皮质醇分泌模式不仅影响睡眠，还可能导致情绪不稳定和认知功能障碍。慢性压力导致的皮质醇调节紊乱已被证明与多种生理和心理疾病密切相关，包括神经退行性疾病和精神障碍 82。
  2. 促肾上腺皮质激素释放激素（CRH）过度分泌： CRH是HPA轴的起始点，在抑郁症患者中，CRH的过度分泌是一个普遍的发现 8186。中枢神经系统中的CRH神经元过度活跃，导致CRH水平升高，进而驱动HPA轴下游的ACTH和皮质醇的过度释放 86。CRH不仅是调节应激反应的激素，还在大脑中发挥神经递质和神经调节剂的作用，其在中央神经系统中的分布及其对焦虑样行为的诱导作用提示CRH在情绪障碍病理生理学中的关键作用 868788。抑郁症患者脑脊液中的CRH浓度升高，垂体ACTH对CRH的反应减弱，以及额叶皮层CRH受体密度降低等，都支持了下丘脑和外下丘脑CRH神经元超分泌的假说 86。
  3. 负反馈机制受损： 在抑郁症中，HPA轴的负反馈机制往往受损，这意味着即使皮质醇水平升高，也无法有效抑制CRH和ACTH的释放，导致HPA轴的持续性过度激活 8182。这种失调可能涉及边缘系统（特别是海马体）糖皮质激素受体神经元的反馈能力下降 81。持续高水平的皮质醇暴露会对海马体等脑区造成损害，影响神经可塑性，并加剧抑郁症状 89。

HPA轴的过度活跃被认为是MDD发展的关键因素，因此，针对HPA轴不同组分（如CRH1受体拮抗剂、糖皮质激素受体拮抗剂等）的治疗策略正在被研究，以期为抑郁症提供更精准的治疗 83。

围产期激素骤降与产后抑郁的特异性机制

围产期（怀孕和产后）是女性HPA轴和下丘脑-垂体-性腺（HPG）轴发生剧烈变化的时期，这些激素的剧烈波动使得女性在此期间更容易发生情绪障碍，尤其是产后抑郁症（PPD） 9091。

  1. 类固醇激素的急剧变化： 怀孕期间，女性体内的雌激素和孕激素水平显著升高。然而，在分娩后，这些激素水平会急剧下降，特别是在产后24-48小时内 9091。这种如同“撤退”般的激素变化被认为是触发部分女性产后抑郁症的关键因素之一。雌激素对情绪具有调节作用，其水平骤降可能导致神经递质（如血清素）的失衡，从而引发抑郁症状。
  2. HPA轴与应激反应的改变： 围产期女性的HPA轴功能也会发生适应性变化。在怀孕期间，HPA轴的活性会增加，以适应胎儿发育的需要。但产后，HPA轴的恢复可能不完全或出现异常，导致对应激的敏感性增加和情绪调节能力下降 9091。皮质醇水平的持续异常，或对压力的反应性增强，都可能促进PPD的发生 90。
  3. 催产素（Oxytocin）的作用： 催产素是一种与社会联结、母婴依恋和情绪调节密切相关的神经肽。在分娩过程中，通常会使用合成催产素（synOT）来促进宫缩和预防产后出血 9293。然而，有研究提出，分娩过程中使用的合成催产素可能与产后抑郁症的发生或恶化有关，尽管其确切的病理生理机制尚不完全清楚 92。外源性催产素可能干扰内源性催产素系统，影响其在情绪调节中的作用，或者通过其他未知的机制增加PPD的风险 93。
  4. 其他内分泌因素： 甲状腺系统功能异常，特别是产后甲状腺炎，也与产后抑郁症的发生有关 91。此外，神经递质系统（如血清素系统）和炎症标志物的变化也在PPD的生物学机制中发挥作用 91。

综上所述，神经内分泌异常，特别是HPA轴的过度活跃和皮质醇节律紊乱，是抑郁症普遍存在的生物学特征。而在围产期，雌激素和孕激素的急剧下降以及催产素等因素的复杂作用，构成了产后抑郁症特异性的神经内分泌基础。深入理解这些机制，对于开发针对性的干预措施和治疗策略至关重要。

3. 心理社会因素：个体与环境的交互作用

3.1 个体心理特质与应激应对

抑郁症的发生发展不仅与生物学因素有关，更与个体的心理特质及其应对环境应激的方式密切相关。特定的心理特质可以增加个体对抑郁症的易感性，而不良的应激应对策略，尤其是认知偏差，则可能加速和维持情绪障碍。

个体心理特质与抑郁症的预测作用

  1. 人格特征：

    • 神经质 (Neuroticism)：神经质是一种常见的人格特质，表现为倾向于体验消极情绪，如焦虑、抑郁、敌意和脆弱。多项研究证实，神经质是抑郁症的强预测因子，其与抑郁症状、重度抑郁症以及焦虑障碍存在显著的遗传重叠 3994。对神经质进行的全基因组关联研究（GWAS）已识别出136个独立基因座，并发现其与多种精神疾病，包括抑郁症、焦虑症和精神分裂症，存在孟德尔随机化效应 95。神经质不仅直接影响抑郁风险，还可能通过影响应激反应和认知应对方式间接发挥作用。
    • 消极认知风格 (Negative Cognitive Style)：消极认知风格是指个体倾向于以消极、悲观的方式解释事件，并对未来持有负面预期。这种认知偏差被认为是抑郁症的核心脆弱性因素之一 9697。例如，在青少年群体中，消极认知风格与抑郁症状的发生发展密切相关，尤其是在面临学业、外貌和人际关系等领域的问题时 96。它也被认为是童年期情感虐待导致青少年抑郁症状的中介机制 98。
    • 反刍思维 (Rumination)：反刍思维是一种重复性地被动关注自己的抑郁症状、其可能的原因和后果，而不是积极解决问题的一种认知模式 99。反刍思维被认为是抑郁症最强且最持久的风险因素之一 99100。它不仅能放大和延长负面情绪状态，干扰问题解决和工具性行为，还能降低个体对环境变化的敏感性，从而加剧精神病理学 99。在功能性磁共振成像（fMRI）研究中，反刍思维与默认模式网络（DMN）的激活密切相关，特别是DMN的核心区域和背内侧前额叶皮层子系统 101。这意味着反刍思维可能通过影响大脑的自省和自我参照加工网络来维持抑郁状态。

  2. 心理韧性 (Resilience)：心理韧性是指个体在面对压力和逆境时，能够积极适应并恢复的能力 102。高水平的心理韧性被认为是抑郁症的保护因素，与较低的抑郁和焦虑水平以及较高的生活质量相关 102103104。例如，对癌症患者的研究显示，韧性得分越高，焦虑和抑郁得分越低，生活质量得分越高 104。心理韧性涉及多个方面，包括积极的应对策略、自我效能感（Self-efficacy）和解决问题的能力。自我效能感强的人更倾向于认为自己有能力应对挑战，从而减轻压力对情绪的负面影响 103。

慢性心理应激与情绪障碍的加剧路径

  1. 创伤后应激 (PTSD) 与童年虐待： 创伤，特别是童年期的虐待，与青年时期的自杀意念高度相关 105。一项针对中国大学生的研究发现，23.5%的参与者报告曾遭受童年创伤，其中“躯体忽视”占最大比例（31.5%）。在经历过“童年忽视、情感虐待和躯体虐待重叠”的群体中，自杀意念最高（2.0%） 105。这些创伤经历可以导致个体形成消极的认知偏见和应对策略。

  2. 认知偏差（反刍思维）的介导作用：

    • 反刍思维的加剧： 慢性应激和创伤经历往往会增加个体的反刍思维倾向 99106。例如，童年期的情感虐待和同伴欺凌可以预测青少年期反刍思维和消极推论的恶化，而反刍思维（特别是沉思型反刍）则进一步中介了虐待经历与抑郁症状增加之间的关系 98。这意味着创伤通过诱导和强化反刍思维，从而加剧抑郁症状。
    • 负性归因风格 (Negative Attributional Style)： 负性归因风格是指个体倾向于将负面事件归因于内部的、稳定的和普遍的原因（例如“我总是很糟糕”、“一切都会出错”）。研究表明，反刍思维与负性归因风格之间存在复杂关系，尤其是在伴有抑郁症状时。在分析性自我聚焦（一种反刍模式）的条件下，负性归因风格与抑郁症状水平的正相关关系更强，提示反刍思维的加工模式可以与抑郁症状相互作用，共同激活负性归因风格 107。
    • 神经生物学基础： 反刍思维与DMN的激活密切相关，尤其是在涉及自我参照和情绪调节的脑区 101。持续的DMN过度活跃和功能连接异常被认为是抑郁症的神经影像学特征之一。当个体经历慢性压力或创伤时，这些认知偏差可能会通过改变大脑的结构和功能，进一步损害情绪调节能力，形成恶性循环。

综上所述，个体心理特质如神经质和消极认知风格，以及不良的应激应对策略如反刍思维，均是抑郁症的重要风险因素。童年虐待等慢性心理应激通过加剧这些认知偏差，特别是反刍思维，从而促使情绪障碍的发生和维持。同时，心理韧性则能有效缓冲这些负面影响，强调了培养积极心理特质在抑郁症预防和干预中的重要性。

3.2 社会支持与人际关系

社会支持和人际关系在抑郁症的发生发展中扮演着举足轻重的角色，它们既可以是抵御抑郁的保护性因素，也可能在缺失或负面时成为重要的风险因素。全球及中国的研究均强调了社会联系质量对心理健康的影响。

低社会支持与抑郁风险的增加

低社会支持是抑郁症的强风险因素。多项研究表明，缺乏社会支持会显著增加抑郁症状和抑郁症的发生率。例如，一项针对韩国女性的研究显示，中度或低水平社会支持的女性更可能患有产后抑郁症（OR=1.78和OR=2.76），尤其是在多产、流产史、肥胖体型和在职女性中这一趋势更为明显 108。另一项针对中国医学生的调查发现，社会支持与抑郁和焦虑症状之间存在显著的负相关，即社会支持越低，抑郁和焦虑症状越严重 109。即使在像中风患者这样的特殊群体中，社会支持也被发现与抑郁呈负相关，更多的社会支持能够降低中风后抑郁的发生率 110。

负面人际互动与社交隔离

  1. 孤独感（Loneliness）：孤独感是一种主观感受，指个体感受到的人际关系质量或数量与期望不符。研究显示，孤独感与抑郁症状之间存在明确的纵向关联。一项为期五年的追踪研究发现，孤独感能预测后续抑郁症状的变化，但抑郁症状不能预测后续孤独感的变化，且这种关联独立于人口统计学变量、客观社会隔离、气质性消极情绪、压力或社会支持 111。在老年人中，孤独感与抑郁症密切相关，并且社交网络的大小和类型在这种关系中发挥作用 112。
  2. 社会隔离（Social Isolation）：社会隔离指客观上缺乏社会联系。虽然孤独感是主观感受，社会隔离是客观状态，但两者均与抑郁风险增加相关 113。社交网络较小的人更容易出现抑郁症状或抑郁症 113。基因组学研究也发现，社会隔离行为的遗传风险与重度抑郁症、神经质、孤独感和自闭症谱系障碍存在遗传相关性 114。
  3. 负面家庭关系：家庭关系，尤其是婚姻状态，对抑郁风险有重要影响。未婚状态（分居/离婚）被认为是女性抑郁症复发的风险因素之一 115。一项针对中国医学生的研究也指出，与恋人或同学朋友关系不好的学生，其抑郁和焦虑评分更高 109。在产后女性中，糟糕的人际关系质量也是围产期抑郁症的风险因素 116。
  4. 社交媒体使用与数字孤独：数字时代带来了新兴的社交互动模式，但也伴随着新的挑战。过度使用社交媒体可能导致青少年和成年人产生“数字孤独”和“信息过载”，增加抑郁风险。尽管目前提供的参考文献未直接详细阐述社交媒体对抑郁症影响的机制，但研究表明，青少年网络成瘾与较少的社会支持、更大的情绪识别和表达困难以及情绪调节障碍相关 117。

高质量社会支持和积极人际关系的保护作用

高质量的社会支持和积极的人际关系对抑郁症具有显著的保护作用。

  1. 总体保护作用：许多研究一致认为，良好的社会支持能够降低抑郁症的风险，并改善抑郁症患者的预后 113118。社会支持的类型多样，包括情感支持、工具性支持、信息支持和评价支持。这些支持能够为个体提供应对压力的资源，增强自我效能感，并促进心理健康。
  2. 围产期女性的社会支持：在围产期，社会支持对预防产后抑郁症至关重要。研究发现，孕期母亲感知到的社会支持能够负向影响产后抑郁，并正向影响出生体验质量。社会支持不仅直接降低产后抑郁风险，还能间接通过改善分娩体验的临床指标来发挥保护作用 119。在早期产后女性中，社会支持水平越高，其抑郁水平越低，而母乳喂养自我效能感越高 120。一项针对中国父母的纵向研究发现，母亲和父亲的社会支持水平在产后6个月内显著下降，同时母亲的产后抑郁水平在产后2-3天最低，在6周、3个月和6个月时均较高，这进一步强调了持续社会支持的重要性 121。
  3. 老年人的社会支持：在亚洲社区居住的老年人中，良好的总体社会支持、拥有配偶或伴侣、与家人同住、拥有更大的社交网络、与家人朋友更频繁的接触、获得情感和工具性支持，以及对社会支持的满意度均与较少的抑郁症状相关 122。与西方文化相比，亚洲文化背景下家庭支持对老年人抑郁症的影响更大，这提示在亚洲背景下干预老年人抑郁症时，需要将家庭机构纳入计划 122。
  4. 特殊疾病人群：在慢性阻塞性肺疾病（COPD）急性加重患者中，社会虚弱与焦虑和抑郁之间没有直接关联，但社会支持在其中起到了中介作用，即增强社会支持可以间接缓解这些患者的焦虑和抑郁 123。

不同文化背景下的体现

社会支持的影响在不同文化背景下可能有所差异。例如，亚洲文化中家庭支持的重要性在老年人群中尤为突出 122。这意味着，在制定干预策略时，需要考虑具体的社会文化环境，以提供最有效和适切的支持。
综上所述，社会支持和良好的人际关系是心理健康的基石。缺乏这些资源，或经历负面的人际互动和社交隔离，都会显著增加抑郁症的风险。因此，加强社会支持系统，促进健康人际关系的建立和维护，是预防和干预抑郁症的重要途径。

3.3 社会经济与生活事件冲击

社会经济因素和重大生活事件是影响抑郁症发病率的重要社会心理决定因素。它们通过多种途径对个体的心理健康产生深远影响，既可能作为急性应激源触发抑郁发作，也可能通过长期累积效应增加个体对抑郁症的易感性。

失业与经济压力

失业，特别是长期失业，与精神健康问题之间存在显著的关联，其中抑郁症尤为突出。

  1. 失业与抑郁症发病率： 多项研究表明，失业是抑郁症的一个主要风险因素 124。在中国，一项全国性的流行病学调查发现，失业人群中任何抑郁症的12个月患病率显著高于就业人群，其风险比（OR）高达2.80（95% CI 1.88-4.18）11。这种关联在年轻人中表现得尤为明显，一项系统综述指出，年轻人的失业与心理健康问题密切相关，尽管这种影响在控制了基线心理健康状况后会减弱，但大多数研究（6/8）仍发现失业对心理健康有影响 125。欧洲精神病学协会（EPA）的指导文件也强调，失业是经济危机对精神健康产生负面影响的主要风险因素之一，特别是对工作年龄的男性 124。
  2. 经济压力与脆弱性： 经济危机和经济压力会显著影响人群的精神健康 124126。在经济不确定时期，失业、不稳定的工作条件、负债、不平等的加剧以及住房不稳定等因素，都会成为抑郁症的风险因素 124。例如，在COVID-19大流行期间，日本的一项研究发现，经历过重大就业相关不利变化（如失业）的个体，其抑郁和焦虑症状更为普遍，尤其是在经济脆弱的女性和男性工人中 126。低收入和未受过大学教育的个体也更容易受到经济冲击对精神健康的影响 126。
  3. 长期影响与干预： 失业对精神健康的负面影响是持续的，而并非短暂的适应性反应 127。针对失业人群的干预研究表明，认知行为疗法（CBT）和工作相关干预措施对减轻抑郁和焦虑症状具有最可靠的证据支持 128。这提示，在应对失业和经济压力时，除了提供经济支持外，心理干预和社会支持同样重要。

教育水平与社会经济地位

教育水平是社会经济地位（SES）的重要组成部分，与抑郁症发病风险之间存在复杂关系。

  1. 教育水平与抑郁： 较低的教育水平通常与较高的抑郁症风险相关。在中国农村地区的一项研究中，教育年限（作为社会经济地位的指标之一）与抑郁症风险之间存在关联 129。这可能因为教育水平较低的个体往往面临更多的经济困难、职业发展受限以及社会支持网络相对薄弱等问题。
  2. 社会经济地位差异： 低社会经济地位（SES）被认为是抑郁症的重要风险因素 124。贫困、低收入、不平等以及缺乏基本社会保障等，都可能增加个体遭受慢性压力和心理负担，进而导致抑郁症的发生 129。在收入不平等加剧的社会中，低收入人群的抑郁风险更高，因为他们可能面临更大的经济压力和心理负担。

重大生活事件的急性触发与长期累积效应

重大生活事件，如亲人离世、职业挫折、婚姻破裂、疾病诊断等，能够作为急性应激源触发抑郁发作，并且其累积效应可能导致长期的抑郁风险 130。

  1. 急性触发效应： 许多抑郁发作的起始点可以追溯到某个重大的负面生活事件。这些事件通常对个体造成巨大的心理冲击，超出了其当前的应对能力，导致情绪失衡。例如，负面生活事件能够影响个体患疾病的风险，其中对精神健康的负面影响显著，特别是那些缺乏社会支持的个体，在经历生活事件时更容易出现负面健康结果 130。
  2. 累积效应： 经历多个负面生活事件，即使是那些单独看起来不那么严重的事件，也可能产生累积效应，逐渐侵蚀个体的心理资源，使其对未来的应激事件变得更加脆弱，从而增加抑郁症的长期风险 130。例如，长期的职业挫折、家庭冲突、经济困境等一系列不良事件的叠加，可能导致个体陷入持续的绝望感和无助感，最终发展为抑郁症。
  3. 社会决定因素的放大效应： 社会决定因素（SDoH）如教育、就业和社区参与等，能够调节和解释性别在抑郁症发生中的差异 131。在面对重大生活事件时，脆弱的社会经济地位和缺乏社会支持的个体，其抵御负面影响的能力更弱，因此更容易受到冲击。例如，分居、丧偶或离婚的人群，其抑郁症的终生患病率和12个月患病率均高于已婚或同居人群，风险比（OR）分别为1.87和1.85 11。这表明婚姻状态（作为一种社会支持形式）的改变或丧失，是重要的生活事件，能够显著增加抑郁风险。

综上所述，社会经济因素和重大生活事件是抑郁症发生发展的关键驱动力。失业、经济压力和较低的社会经济地位使得个体更易遭受心理健康问题，而重大生活事件则可能直接触发或通过累积效应加重抑郁症状。因此，在抑郁症的预防和干预策略中，除了关注生物学和心理学因素外，还必须充分考虑这些社会经济和环境层面的影响。

4. 共病与特殊场景：多疾病交织的复杂致病网络

4.1 躯体疾病共病的双向影响

抑郁症常与其他躯体疾病共病，这种共病关系并非简单的伴随，而是存在复杂的双向影响机制。躯体疾病不仅可以诱发抑郁，抑郁反过来也会加剧躯体疾病的进展和不良预后。这种“你中有我，我中有你”的复杂交织网络，极大地增加了疾病负担和治疗难度。

神经退行性病变与脑损伤对抑郁的诱发机制

神经退行性疾病和脑损伤是抑郁症的重要危险因素。这类疾病通过直接损伤神经结构、改变神经递质平衡、引发炎症反应等多种机制，诱导抑郁情绪的产生。

  1. 帕金森病（PD）： 抑郁是帕金森病常见的非运动症状之一，有时甚至可能早于运动症状出现，成为帕金森病的早期预警信号 132。帕金森病患者抑郁的发生机制复杂，涉及多巴胺能神经元丢失导致的黑质纹状体通路功能障碍，以及其他神经递质系统（如5-羟色胺、去甲肾上腺素）的失衡。此外，帕金森病患者大脑中α-突触核蛋白的错误折叠和聚集可能导致神经炎症和氧化应激，这些生物学过程也被认为与抑郁症的发生发展有关。神经炎症和神经变性过程均可损害大脑的情绪调节网络，从而诱发抑郁 132。

  2. 脑卒中后抑郁（PSD）： 脑卒中后抑郁（PSD）是脑卒中后最常见的精神障碍之一，其发生率高达18%至33% 133，并显著影响患者的康复、认知功能和生活质量 133134。PSD的病理生理学是多因素的，涉及脑损伤的解剖位置和大小，以及神经生物学改变。

    • 脑损伤定位： 卒中病灶的位置对PSD的发生有重要影响。额叶/前部区域或基底节区的较大或多发性卒中损伤与PSD的风险增加相关 133。这些区域与情绪调节和执行功能密切相关，其损伤可能直接导致抑郁症状。
    • 神经递质失衡： 卒中引起的局部缺血和神经元损伤可导致单胺类神经递质（如5-羟色胺、去甲肾上腺素和多巴胺）水平下降 133135，这被认为是PSD发生的核心机制之一。
    • 神经炎症与HPA轴： 卒中急性期可引发显著的神经炎症反应，小胶质细胞和星形胶质细胞被激活，释放大量促炎细胞因子。这些炎症介质可以影响神经元的存活和功能，并可能导致下丘脑-垂体-肾上腺（HPA）轴的功能紊乱，进而诱发抑郁 133135。HPA轴的失调、皮质醇节律紊乱已被认为是抑郁症的重要生物学标志。
    • 神经可塑性改变： 卒中后脑损伤还会影响神经可塑性，包括神经发生、突触重塑等，这些改变被认为在PSD的发生中发挥作用 134。

慢性疼痛的炎症反应与抑郁

慢性疼痛和抑郁症之间存在高度共病性，且两者之间是双向关系 136137。神经炎症被认为是连接疼痛和抑郁共病的关键机制之一 138。

  1. 共同的神经机制： 慢性疼痛和抑郁症共享许多神经环路和生物分子通路 136。功能影像学研究表明，慢性疼痛和精神健康障碍之间存在的双向关系部分是由于共享的神经机制 136。
  2. 炎症介导： 慢性疼痛状态下，持续的炎症反应会导致外周和中枢神经系统中的促炎细胞因子水平升高。这些细胞因子可以激活小胶质细胞，加剧神经炎症，并影响神经递质的合成和释放，特别是色氨酸-犬尿氨酸代谢途径的改变。炎症会刺激犬尿氨酸途径中的某些酶，同时抑制另一些酶，导致神经毒性代谢产物（如喹啉酸）增加，而神经保护性代谢产物（如犬尿酸）减少，这被认为在慢性疼痛和抑郁症的病理生理学中发挥关键作用 138。
  3. HPA轴与应激： 慢性疼痛本身就是一种长期的应激源，可导致HPA轴的慢性激活和功能失调，进而诱发或加重抑郁症状。

抑郁对躯体疾病预后的反向影响

抑郁症不仅是一种精神障碍，还会对多种躯体疾病的预后产生负面影响，甚至增加死亡率。

  1. 心血管疾病（CHD）： 抑郁症是冠心病（CHD）发病以及心血管疾病患者发病率和死亡率升高的重要危险因素 139。抑郁与肥胖也存在双向关系，且共享许多生物学机制，包括遗传、HPA轴改变、免疫炎症激活以及能量代谢相关神经内分泌调节因子（如瘦素和胰岛素）的异常 140。在CHD患者中，抑郁症状的改善可以显著改善心血管事件的预后 139。一项研究显示，抑郁症的严重程度与心肾代谢（CKM）综合征的进展和全因死亡率增加独立相关 141。
  2. 癌症： 重度抑郁症在癌症患者中普遍存在，其患病率是普通人群的四倍之多 142。抑郁症会加剧癌症的恶性进程，导致患者对治疗的依从性降低，并增加死亡率 142。生物行为机制，如炎症、氧化应激、免疫功能下降以及自主神经系统和HPA轴的失调，被认为是抑郁症促进癌症进展的重要途径 142。
  3. 其他躯体疾病： 抑郁症还与多种慢性躯体疾病（如糖尿病、慢性肾病、呼吸系统疾病等）的预后不良相关。抑郁症患者通常依从性较差，生活方式不健康（如吸烟、缺乏运动、不良饮食），这些都会进一步加重躯体疾病的负担。

综上所述，躯体疾病与抑郁症之间的双向影响是一个复杂且广泛的现象。理解这些相互作用的机制，对于开发综合性的诊断、预防和治疗策略，改善患者的整体健康状况具有重要意义。

4.2 精神障碍共病的叠加风险

抑郁症很少单独存在，它常常与其他精神障碍共病，形成复杂的临床图景。这种共病不仅加剧了症状的严重性、增加了治疗难度，还可能导致疾病慢性化，显著影响患者的生活质量。焦虑障碍和双相情感障碍是抑郁症最常见的共病精神障碍，它们之间存在着症状重叠和病理共享的复杂关系。

焦虑障碍与抑郁症的症状重叠及病理共享

焦虑障碍与抑郁症的共病率极高，并且两者在临床表现和潜在生物学机制上存在显著的重叠。

  1. 症状重叠： 焦虑障碍和抑郁症都可能表现出核心症状，如睡眠障碍、疲劳、注意力不集中、易激惹以及躯体症状（如心悸、胸闷等）。这使得临床诊断变得复杂，有时难以区分是哪种疾病占据主导地位，或是同时存在。例如，广泛性焦虑障碍（GAD）患者常伴有抑郁情绪，而重度抑郁症患者也常常体验到显著的焦虑。
  2. HPA轴异常： HPA轴（下丘脑-垂体-肾上腺轴）功能失调是抑郁症和焦虑障碍共同的病理生理基础之一 143144。早期生活应激（如童年创伤）可导致HPA轴的持续性激活和功能障碍，从而增加个体患焦虑症和抑郁症的风险 143。高水平的皮质醇分泌、皮质醇昼夜节律紊乱以及糖皮质激素受体功能受损，在两类疾病中均有体现 143。HPA轴的持续激活会影响情绪调节中枢，如杏仁核和前额叶皮层，导致情绪失调。
  3. 神经可塑性降低： 焦虑和抑郁症患者均可能表现出神经可塑性降低，尤其是在涉及情绪调节和认知功能的脑区。例如，慢性应激可导致前额叶皮层对杏仁核的调控失衡，进而引发焦虑样行为 145。这种神经可塑性的降低使得大脑应对压力的能力下降，并难以从负面情绪中恢复。
  4. 肠道微生物-脑轴： 近年来研究表明，肠道微生物-脑轴在焦虑和抑郁的共病中也发挥着作用。系统综述指出，焦虑和抑郁症患者的肠道菌群可能表现出促炎性菌种的丰度较高，而产生短链脂肪酸（SCFAs）的益生菌丰度较低 62。肠道菌群失调通过影响神经递质（如5-羟色胺）合成、免疫激活和HPA轴功能，从而共同影响情绪状态。

双相情感障碍与抑郁症的复杂关系

抑郁症是双相情感障碍患者面临的一个主要挑战，导致巨大的疾病负担 146。双相抑郁与单相抑郁在临床表现上有很多相似之处，但治疗策略和预后却大相径庭，因此准确识别共病至关重要。

  1. 症状重叠与鉴别诊断： 双相抑郁与单相抑郁在症状学上存在高度重叠，例如情绪低落、快感缺失、精力不足、睡眠和食欲紊乱等。然而，双相抑郁通常伴有更多的非典型特征，如睡眠过多、食欲增加、铅样麻痹（肢体沉重感），以及精神运动性迟滞等。此外，双相抑郁患者往往有躁狂或轻躁狂发作史，这是与单相抑郁的关键区别。
  2. 病理共享： 双相情感障碍和抑郁症在遗传学上存在一定的重叠，均涉及情绪调节、应激反应和神经可塑性相关的基因。HPA轴功能异常在双相情感障碍中也普遍存在，尤其是在抑郁发作期，其与应激反应和疾病复发密切相关 147。此外，神经炎症和氧化应激也被认为是双相情感障碍的病理机制之一，这些也与抑郁症的发生发展有关。
  3. 对治疗难度和疾病慢性化的影响：
    • 药物反应差异： 治疗双相抑郁比治疗单相抑郁更具挑战性。尽管抗抑郁药可能对双相抑郁有效，但其在治疗双相抑郁中的有效性和安全性仍存在争议 146。尤其是在双相I型障碍（BD-1）患者中，单独使用抗抑郁药可能会诱发躁狂或轻躁狂转相，或导致快速循环，因此通常建议与心境稳定剂或抗精神病药物联合使用 146。双相II型障碍（BD-2）患者对抗抑郁药的耐受性优于BD-1患者，尤其是在与心境稳定剂或抗精神病药物联合使用时 146。
    • 疾病慢性化： 双相情感障碍的共病抑郁常导致疾病病程更加复杂和慢性化。由于症状的反复发作和治疗的挑战性，患者的功能损害更大，生活质量更低，复发率也更高。对双相抑郁的长期管理，特别是长期维持治疗，仍是临床研究的重点 146。
    • 边缘型人格障碍共病： 边缘型人格障碍（BPD）也常与重度抑郁症共病。BPD患者常伴有情绪和冲动失调、不稳定的自我认知以及人际关系困难，并常有自杀和自伤行为 148。当BPD与MDD共病时，两种疾病应同时治疗。研究表明，在这种情况下，MDD对BPD的结局预测不明显，但BPD却是MDD结局的重要预测因素 148。此外，BPD共病的MDD对抗抑郁药物的反应不如无BPD的MDD患者 148。

共病对治疗和预后的影响

抑郁症与其他精神障碍的共病显著增加了治疗的复杂性。由于症状重叠，诊断往往延迟或不准确，导致治疗方案选择不当。例如，将双相抑郁误诊为单相抑郁而单独使用抗抑郁药，可能加重病情或诱发不良事件。共病还会导致治疗依从性下降、副作用增加以及治疗反应不佳，从而增加疾病慢性化的风险，并带来更大的社会和经济负担。因此，在评估和治疗抑郁症患者时，全面筛查共病精神障碍至关重要，以便制定个体化、综合性的治疗方案。

4.3 特殊场景下的抑郁易感性

抑郁症并非在所有生命阶段都以相同的模式发生，而是与特定的生命阶段和相应的情境因素紧密相关。围产期、青春期和老年期是三个关键的生命阶段，个体在这些时期面临着独特的生理、心理和社会挑战，从而使其对抑郁症表现出更高的易感性。

围产期女性：产后抑郁的特异性风险

围产期（包括怀孕期和产后一年）是女性发生抑郁症的高风险时期。全球范围内，产后抑郁症的总体患病率为17% 149，最高可达19.2%（主要抑郁发作占7.1%）150。一项纳入了315名女性的横断面研究显示，筛查提示有19.7%的患者患有抑郁症 151。即使是没有抑郁史的健康母亲，产后抑郁症的发生率也达到12%，而总体患病率为17% 149。

围产期抑郁症的特异性致病机制主要包括：

  1. 激素的剧烈变化： 怀孕期间，女性体内的雌激素和孕激素水平显著升高。然而，在分娩后，这些激素水平会急剧下降，尤其是在产后24-48小时内。这种如同“撤退”般的激素变化被认为是触发部分女性产后抑郁症的关键因素之一 152 153。雌激素对情绪具有调节作用，其水平骤降可能导致神经递质（如血清素）的失衡，从而引发抑郁症状 91。
  2. 促乳素和催产素： 泌乳期间，高水平的催乳素和催产素以及低水平的血管加压素和雄激素可能对激素敏感的母亲产生积极的情绪作用，从而降低产后抑郁和焦虑的发生率 154。然而，分娩期间使用合成催产素与产后抑郁症的发生或恶化可能存在关联，尽管确切的病理生理机制尚不完全清楚。
  3. HPA轴功能失调： 围产期女性的下丘脑-垂体-肾上腺（HPA）轴功能也会发生适应性变化。产后，HPA轴的恢复可能不完全或出现异常，导致对应激的敏感性增加和情绪调节能力下降。持续的皮质醇水平异常，或对压力的反应性增强，都可能促进PPD的发生 152。
  4. 遗传易感性： 存在激素-基因和激素-环境相互作用，这些可能决定最终的心理结果 154。
  5. 社会和心理因素： 除了生理因素，社会心理因素也在产后抑郁症的发生中扮演重要角色。低家庭收入、多产、产前检查次数少、情绪障碍史、对怀孕不满意、与伴侣关系不佳以及心理攻击等都是与围产期抑郁症相关的风险因素 151。社会支持的缺乏，尤其是来自配偶和家庭的支持不足，以及分娩体验不佳等，都会增加产后抑郁的风险 155。新生儿的到来也意味着社会角色的巨大转变，新手妈妈需要适应新的身份、照料责任、睡眠剥夺和社交活动减少等，这些都可能构成巨大的心理压力。

青春期：生理与心理双重挑战

青春期是生理和心理发展剧烈变化的时期，也是抑郁症发病的高峰期之一。青少年面临精神健康问题，包括抑郁症的脆弱性增加 156。

  1. 生理发育： 青春期大脑的快速发育，特别是前额叶皮层（负责决策、情绪调节等）的重塑，以及性激素水平（如雌激素、雄激素）的波动，都可能影响情绪的稳定性，增加抑郁的易感性。
  2. 学业压力与同伴关系： 青少年面临日益增加的学业压力、升学竞争，以及复杂的同伴关系挑战。在大学阶段，学业表现、成功压力和毕业后规划是学生最关心的三大问题，这些问题与更高的压力、焦虑和抑郁水平相关 157。社交排斥、欺凌等负面同伴互动，可能导致自尊心下降，诱发抑郁情绪。
  3. 身份认同与自我探索： 青春期是青少年寻求自我认同和价值观形成的关键时期。在这一过程中，他们可能经历自我怀疑、困惑和迷失，如果缺乏积极的引导和支持，可能导致情绪困扰。
  4. 生活方式因素： 青少年时期的不良生活习惯，如睡眠障碍、缺乏体育活动和不健康的饮食模式，都与抑郁症的发生发展密切相关 158。夜间电子媒体使用、睡眠质量差等因素可以部分介导电子媒体使用与抑郁症状之间的关系 156。
  5. 童年创伤： 童年期的逆境经历，如虐待和忽视，与青少年期的抑郁症状高度相关，并能增加成年期自伤行为的风险 159。
  6. 社交媒体使用： 短视频应用（如TikTok）的过度使用或成瘾性使用与青少年较差的心理健康状况相关，包括更高的抑郁、焦虑、压力、孤独感和较低的生活满意度及睡眠质量 160。然而，适度的社交媒体使用可能不与负面心理健康状况相关 160。

老年期：孤独与社会功能退化的影响

老年期（60岁以上）是抑郁症的另一个高发阶段。抑郁症在老年人中普遍，是导致老年人情感痛苦的最常见原因之一，并显著降低老年人的生活质量 161。

  1. 生理退化与慢性疾病： 随着年龄增长，身体机能逐渐下降，慢性疾病的患病率显著增加。身体疾病本身就是抑郁症的风险因素，且疾病带来的疼痛、功能障碍和生活质量下降，会进一步加重心理负担。抑郁症与老年人的全因死亡率和心血管疾病死亡率的风险增加相关 12。
  2. 社会角色转变： 退休是老年期一个重大的社会角色转变。退休可能导致社会活动减少、社交网络缩小、经济收入下降，以及自我价值感降低，从而增加抑郁风险。
  3. 亲友丧失与孤独感： 老年人面临亲友（如配偶、朋友）离世的风险更高，丧失带来的悲痛和孤独感可能增加抑郁风险。
  4. 认知功能障碍： 抑郁症本身可以导致认知功能下降，而认知功能下降也会增加老年人患抑郁症的风险，两者之间存在复杂的双向关系。
  5. 睡眠障碍： 许多老年人饱受失眠困扰。认知行为疗法（CBT-I）治疗失眠可有效预防老年人重度抑郁症的发生和复发，提示睡眠障碍在老年抑郁症中的关键作用 162。

综上所述，围产期、青春期和老年期因其独特的生理、心理和社会特征，使得个体在这些生命阶段更容易受到抑郁症的影响。了解这些特异性的致病机制，有助于为这些特殊人群制定更具针对性的预防、筛查和干预策略。

5. 环境与行为因素：生活方式与外部暴露的长期作用

5.1 生活方式相关风险

生活方式，作为个体与环境互动的日常体现，对抑郁症的发生发展具有长期且深远的影响。体力活动水平、睡眠模式以及饮食习惯不仅是健康的晴雨表，更通过复杂的生物学通路与情绪调节紧密关联。

体力活动（Physical Activity）

体力活动不足已被确认为是抑郁症的重要风险因素。相反，规律的体育锻炼被广泛认为是预防和辅助治疗抑郁症的有效手段 163。

  1. 低活动量与抑郁风险： 研究表明，体力活动量低的人群患抑郁症的风险显著升高。一项荟萃分析发现，与高体力活动水平者相比，低体力活动水平者患抑郁症状的风险高出47%（OR=1.47） 。这种关联在青少年群体中同样存在。一项针对中国青少年的研究显示，较低的体力活动水平与抑郁症状呈负相关 164。久坐行为和缺乏体育活动显著影响抑郁症的发生 163。
  2. “运动-脑-情绪”通路： 体育锻炼通过多种神经生物学机制发挥抗抑郁作用：
    • 脑源性神经营养因子（BDNF）释放增加： BDNF是一种在神经元生长、存活和突触可塑性中发挥关键作用的蛋白质，其水平降低与抑郁症的发生密切相关。体育锻炼能够显著增加BDNF的产生和释放 165166，尤其是在抑郁症患者中，运动被发现能可靠地提高BDNF水平 165。BDNF的增加有助于促进神经发生（特别是在海马区）、增强突触连接和改善神经可塑性，从而改善情绪调节功能 165166。
    • 神经递质调节： 运动能够调节多种神经递质的水平，包括5-羟色胺、去甲肾上腺素和多巴胺等，这些神经递质在情绪和奖赏回路中发挥核心作用。增加这些神经递质的活性有助于改善情绪、提高动机。
    • 炎症和氧化应激的改善： 规律运动具有抗炎和抗氧化作用，可以降低全身性炎症水平，减少氧化应激对大脑的损害。鉴于炎症在抑郁症中的关键作用，运动的抗炎效应可能通过抑制神经炎症而发挥抗抑郁作用 163。
    • 内源性大麻素系统激活： 运动可以激活内源性大麻素系统，产生类似大麻素的镇痛和抗焦虑效果，从而改善情绪和缓解压力。
    • 心理社会效益： 除了生物学机制，运动还能带来心理社会效益，如提高自我效能感、改善睡眠、促进社交互动（如团体运动），这些都有助于缓解抑郁症状。例如，Otago运动项目（OEP）被认为对老年人的身体功能和心理健康都有益，包括改善认知功能、增强下肢肌肉力量和平衡能力，并有助于改善跌倒效率和克服对跌倒的恐惧 167。

睡眠障碍（Sleep Disturbance）

睡眠障碍，尤其是失眠，与抑郁症之间存在显著的双向关系。它既是抑郁症的常见症状，也是其重要的独立风险因素 168。

  1. 失眠与抑郁风险： 许多纵向研究已证实，失眠是罹患新发或复发抑郁症的独立风险因素，无论年龄大小（青少年、中年人或老年人） 168169。非抑郁症患者失眠，其发展为抑郁症的风险是无睡眠困难者的两倍 169。
  2. 昼夜节律紊乱： 抑郁症患者常伴有昼夜节律紊乱，表现为睡眠-觉醒周期异常、褪黑素分泌节律失调等。昼夜节律的紊乱不仅影响睡眠质量，还可能通过影响HPA轴功能、神经递质系统以及基因表达，从而加重抑郁症状。
  3. 神经生物学机制：
    • 过度觉醒（Hyperarousal）： 慢性失眠的核心特征是持续的生理、认知和情绪过度觉醒。这种过度觉醒状态与HPA轴的过度活跃和皮质醇水平升高有关，进而影响情绪调节 170。
    • 快速眼动睡眠（REM sleep）不稳定： REM睡眠在情绪加工和记忆巩固中扮演重要角色。失眠患者的REM睡眠可能表现出不稳定性，这可能导致情绪处理障碍，并解释了失眠与抑郁、焦虑之间密切关联。REM睡眠的不稳定性可能导致醒来时更像清醒状态，反映睡前担忧，从而促进负面情绪 170。
    • 炎症与神经递质： 睡眠不足可导致促炎细胞因子水平升高，加剧炎症反应，影响神经递质平衡。
  4. 治疗与干预： 认知行为疗法（CBT-I）被认为是治疗失眠的有效非药物疗法，并已被证明能有效改善共病的抑郁和焦虑症状 171172。针对睡眠障碍的早期干预可能有助于降低普通人群患抑郁症的风险，被视为心理健康护理领域有效的预防策略 169。

饮食模式（Dietary Patterns）

饮食质量与抑郁症风险密切相关，健康的饮食模式具有抗抑郁作用，而不健康的饮食模式则可能增加抑郁风险。

  1. 高质量饮食的保护作用： 大量研究表明，坚持高质量的膳食模式（如地中海饮食、健康/审慎饮食）与较低的抑郁症状风险相关 173174。这些饮食模式通常富含蔬菜、水果、全谷物、鱼类、坚果和橄榄油等，且以线性剂量-反应方式降低抑郁风险 173。
  2. 抗炎饮食： 饮食的炎症潜力与抑郁症风险相关。促炎饮食（如富含精制谷物、加工食品、红肉和含糖饮料的饮食）与抑郁症风险增加相关，而抗炎饮食（如富含蔬菜、水果、鱼类和全谷物的饮食）则能降低风险 166174175。一项荟萃分析发现，促炎饮食与抑郁症或抑郁症状风险增加40%相关 175。
  3. “饮食-菌群-代谢”轴： 肠道微生物群及其代谢产物在连接饮食和情绪之间扮演着关键角色，形成“肠道-脑轴” 166。
    • 肠道菌群多样性： 健康的饮食，尤其是富含膳食纤维的饮食，可以促进肠道菌群的多样性和益生菌的生长，产生短链脂肪酸（SCFAs）等有益代谢产物。这些代谢产物可以通过多种途径影响大脑功能，包括调节神经递质（如5-羟色胺）的合成、改善炎症反应、影响HPA轴活性，从而影响情绪和认知 176177178。例如，高纤维饮食能改善2型糖尿病患者的肠道菌群、血清代谢和情绪，增加双歧杆菌属、粪杆菌属和普雷沃氏菌属等有益菌的丰度，并减少机会致病菌 176。
    • 益生菌补充： 益生菌补充剂已被证明能改善健康老年人的认知功能和情绪，同时改变肠道菌群组成，减少炎症相关肠道细菌，并增加血清BDNF水平 179。
    • 膳食炎症指数（DII）： DII较高的促炎饮食与抑郁症风险增加相关 177。一项研究发现，仅肠道菌群饮食指数（DI-GM）与伴有自杀意念的重度抑郁症（MDD+SI）呈显著负相关，提示通过饮食干预改善肠道菌群多样性可能有助于降低MDD+SI的风险 177。
  4. 不健康饮食模式： “西方饮食”（Western diet），通常指富含加工食品、精制谷物、高糖产品、油炸食品和红肉的饮食，与更高的抑郁症状风险相关 174。超加工食品、汽水以及罐头和冷冻食品的摄入与抑郁症风险增加相关，且这种关联在不同性别和年龄组中存在差异 180。

综上所述，体力活动、睡眠和饮食模式是与抑郁症密切相关的关键生活方式因素。通过促进规律运动、改善睡眠卫生和采纳健康饮食模式，可以有效调节“运动-脑-情绪”通路和“饮食-菌群-代谢”轴，从而降低抑郁症的发生风险并改善其症状。

5.2 环境暴露与社会变迁

环境暴露，尤其是空气污染和噪音，以及快速的社会变迁，如城市化进程和家庭结构小型化，对抑郁症的发生发展具有不可忽视的长期影响。这些外部因素通过诱导生理应激、炎症反应，并瓦解传统的社会支持系统，从而增加人群的抑郁风险。

空气污染：氧化应激与炎症反应诱发抑郁的潜在机制

空气污染，特别是细颗粒物（PM2.5）和氮氧化物（NOx）等，已被证明与神经精神疾病的风险增加相关，包括抑郁症 181182。

  1. 氧化应激机制： 空气污染物，特别是PM2.5，含有大量活性氧物质或能够诱导活性氧物质（ROS）的产生。当这些污染物被吸入并进入血液循环时，它们可以在大脑中引起氧化应激，导致神经细胞损伤和功能障碍 181183。氧化应激是抑郁症病理生理学中的一个重要环节，通过损害神经元、影响神经递质平衡和神经可塑性来促进抑郁症的发生。研究发现，环境PM2.5可以通过Nrf2/NLRP3信号通路调节炎症，从而导致抑郁样反应 183。Nrf2是体内重要的抗氧化转录因子，其功能受损会加剧氧化应激对神经系统的影响。
  2. 炎症反应机制： 空气污染物被认为是引发系统性炎症的重要环境诱因 181。当吸入的颗粒物进入肺部并被巨噬细胞吞噬后，会诱导促炎细胞因子（如IL-6、TNF-α）的释放，这些炎症因子可以穿过血脑屏障，激活大脑中的小胶质细胞和星形胶质细胞，从而引发神经炎症 181184。神经炎症导致海马神经发生受损、前额叶皮层功能异常，并影响神经递质（如5-羟色胺和多巴胺）的代谢，最终诱发或加重抑郁症状 181184。例如，PM2.5暴露已被发现与皮质醇水平、血清素和多巴胺含量的改变有关，这些都是抑郁症的关键生物标志物 183。
  3. HPA轴功能障碍： 慢性暴露于空气污染物可能导致下丘脑-垂体-肾上腺（HPA）轴的过度激活和功能紊乱，表现为皮质醇水平升高和应激反应增强。HPA轴的失调是抑郁症重要的神经内分泌机制之一 181185。
  4. 遗传易感性与环境交互作用： 孟德尔随机化（MR）分析提供了空气污染物与精神障碍之间因果关系的新证据。研究表明，遗传预测的氮氧化物（NO）与重度抑郁症风险增加有关（OR: 1.13），遗传预测的PM2.5与重度抑郁症风险增加有关（OR: 1.21） 182。此外，孕期PM暴露与后代神经精神障碍（如认知障碍、ASD、ADHD、焦虑和抑郁）的发展相关，这可能通过系统性炎症、氧化应激和肠道-脑轴紊乱等机制发生 186。空气污染不仅是抑郁症的独立风险因素，还会加剧重度抑郁症的严重程度，尤其是在低温环境下或对空气污染敏感的个体中更为显著 187。
  5. 噪音污染： 环境噪音，特别是交通噪音，也被认为是精神障碍的风险因素之一，包括抑郁症和焦虑症 184188。噪音可以通过引起睡眠障碍、增加生理应激反应和干扰认知功能来影响心理健康。

社会变迁对传统支持系统的冲击及其对抑郁发病率的影响

快速的社会变迁，尤其是城市化进程和家庭结构小型化，对个体，特别是脆弱人群的心理健康产生了深远的影响，部分原因是它们削弱了传统的社会支持系统。

  1. 城市化进程：
    • 生活压力增加： 城市化通常伴随着生活节奏加快、竞争加剧、经济压力增大、交通拥堵和居住空间有限等问题，这些都可能成为慢性应激源，增加城市居民的抑郁风险 188。
    • 社会凝聚力下降： 城市化可能导致社区联系减弱，人际关系疏远，从而削弱传统的社会支持网络。在城市环境中，个体可能感到更加孤立和匿名，缺乏归属感，这与抑郁症的发生密切相关。
    • 环境因素叠加： 城市地区通常伴随着更高的空气污染和噪音水平，这些环境暴露与上述的生物学机制相互作用，进一步增加了城市居民的抑郁风险 184188。
    • 移民与适应挑战： 大量农村人口涌入城市，面临文化适应、就业不稳定、社会融入困难等挑战，这些都是重要的心理应激源，可能增加移民群体的抑郁风险 189。
  2. 家庭结构小型化与传统支持瓦解：
    • 家庭支持减少： 传统的大家庭模式逐渐被核心家庭甚至单身家庭取代，导致家庭成员之间的情感支持、物质援助和照料功能减弱。对于老年人、儿童和青少年等需要较多支持的群体，家庭支持的减少会显著增加他们的脆弱性 190。例如，在老年人中，低社会支持是抑郁症的风险因素 190191。
    • 代际关系疏远： 家庭结构的变化可能导致代际关系的疏远，削弱了老年人获得子女照料和情感慰藉的渠道，从而增加孤独感和抑郁风险。
    • 女性精神健康负担： 尽管女性在生理上并未必然承担更多照护责任，但在社会文化背景下，女性可能在家庭照护方面面临较大压力，尤其在缺乏足够社会支持时，这可能增加其精神健康负担，例如抑郁风险的增加 192。
    • 社会心理因素： 失业、分居/离婚、低社会经济地位和慢性疾病等社会心理因素也可能是抑郁症的风险因素。

综上所述，空气污染和噪音等环境暴露通过氧化应激和炎症反应等生理机制，直接或间接影响大脑功能，增加抑郁症的风险。同时，城市化进程和家庭结构小型化等社会变迁，削弱了传统的社会支持系统，使个体面临更多心理应激和更少的保护因素，从而提升了抑郁症的流行率。这些复杂的环境与社会因素交织，共同构成了抑郁症发病的多维度风险网络。

5.3 数字时代的新兴挑战

数字时代的到来深刻改变了人们的生活方式、社交模式和信息获取途径，尤其对心理健康，特别是抑郁症的发生发展带来了新兴的挑战。社交媒体的普及和电子屏幕时间的增加，在青少年和成年群体中引发了“数字孤独”和“信息过载”等现象，这些因素都可能加剧抑郁风险。

社交媒体使用与抑郁风险

社交媒体（Social Media, SM）已经成为现代生活中不可或缺的一部分，但其过度使用与抑郁症之间的关联日益受到关注。

  1. 社交媒体使用与抑郁： 多项研究表明，社交媒体使用与抑郁症之间存在显著关联，特别是对于年轻成年人而言。一项针对1,787名19至32岁美国年轻成年人的调查显示，与社交媒体使用时间最少的群体相比，使用时间最多的群体患抑郁症的几率显著增加（AOR = 1.66, 95% CI = 1.14-2.42）193。同样，每周访问社交媒体网站频率最高的个体和全球频率得分较高的个体，患抑郁症的几率也显著升高193。这种关联呈现出强烈的线性剂量-反应趋势，即使用越多，抑郁风险越高193。此外，另一项研究发现，过度使用或成瘾性地使用短视频应用（如TikTok）与青少年较差的心理健康状况相关，包括更高的抑郁、焦虑、压力、孤独感和较低的生活满意度及睡眠质量。然而，适度的社交媒体使用可能不与负面心理健康状况相关。

  2. “数字孤独”与社会比较： 社交媒体在提供连接的同时，也可能导致“数字孤独”。用户可能在平台上看到他人展示的“完美”生活，从而产生负面社会比较，感到自身不足或被排斥。这种比较可能加剧自卑感和孤独感，进而增加抑郁风险。研究发现，拒绝敏感性（rejection sensitivity），即对社会拒绝的过度敏感，与抑郁、焦虑和孤独感呈显著正相关，而社交媒体环境可能为这种敏感性提供更多触发点194。尽管社交媒体旨在促进社会连接，但过度使用反而可能导致社会连接感降低，因为虚拟互动无法完全替代真实的面对面交流。孤独感在基线时即与后续抑郁症状的恶化相关，并且这种关联独立于客观社会隔离、社会支持、气质性消极情绪或压力等因素195196。

  3. 信息过载与焦虑： 社交媒体和互联网提供了海量信息，但同时也可能导致信息过载。面对过多的新闻、观点和社交互动，个体可能感到压力和焦虑，难以处理和消化这些信息。持续的信息过载可能导致心理疲劳、注意力分散，并最终影响情绪稳定。

电子屏幕时间与心理健康

电子屏幕时间不仅限于社交媒体，还包括视频游戏、流媒体内容观看等。长时间的屏幕使用，尤其是在青少年群体中，已被证明与多种心理健康问题相关。

  1. 屏幕时间与青少年心理健康： 一项针对青少年的系统性综述发现，大多数研究均认为屏幕暴露与心理健康之间存在关联197。智能手机是青少年最常用的设备，在工作日使用与心理健康状况下降相关197。过度屏幕时间与抑郁症状、焦虑和低自尊显著相关198。例如，一项针对9-10岁儿童的研究发现，更长的屏幕时间与更差的心理健康、更多的行为问题、更低的学业表现和更差的睡眠相关199。

  2. 昼夜节律紊乱与睡眠质量： 夜间使用电子屏幕设备，特别是发出蓝光的屏幕，会干扰褪黑素的分泌，从而影响睡眠质量和昼夜节律198。睡眠障碍是抑郁症的重要风险因素，其与抑郁症之间存在双向关系198。夜间特定的社交媒体使用能够预测较差的睡眠质量，即使在控制了焦虑、抑郁和自尊等因素后，这种关联依然存在198。睡眠质量的下降和昼夜节律的紊乱，进一步加剧了抑郁和焦虑的风险200。

  3. 对注意力和行为的影响： 过度屏幕时间，尤其是观看暴力和快节奏内容，会激活多巴胺和奖赏通路，可能导致注意力不集中、冲动控制问题，并与注意力缺陷/多动障碍（ADHD）相关行为的加剧有关200。虽然ADHD本身并非抑郁症，但其症状常与情绪失调并存，并可能增加抑郁的易感性。

心理机制与干预方向

  1. 心理机制： 数字时代对心理健康的影响是多方面的。除了上述的社会比较、孤独感、信息过载和昼夜节律紊乱外，还可能涉及网络成瘾（如社交媒体成瘾、视频游戏成瘾），这与ADHD、强迫症、焦虑和抑郁症状存在显著关联201。这些成瘾行为可能导致个体对真实生活中的社交互动和应对机制的依赖性降低，进一步削弱心理韧性。
  2. 干预方向：
    • 健康素养与数字干预： 随着数字技术在心理健康领域的应用日益广泛，数字心理健康干预措施（Digital Mental Health Interventions, DMHIs）被认为具有潜力，尤其是在等待治疗期间。然而，患者可能需要具备足够的数字健康素养才能有效参与此类干预202。针对抑郁症和焦虑症的数字健康干预已被证明是可接受且有效的，例如数字认知行为疗法（CBT）和虚拟现实疗法（VRT）203204。这些干预措施通常通过线上平台、移动应用程序等形式提供心理支持和治疗，但需要进一步研究如何提高患者的持续参与度205。
    • 限制屏幕时间与规范使用： 针对青少年，应鼓励家长和教育者引导其合理使用电子设备，限制屏幕时间，特别是夜间使用，以保护睡眠质量。
    • 促进真实社交互动： 鼓励和创造机会让个体进行真实的社会互动，培养面对面沟通的能力，建立和维护健康的社会支持网络，以对抗“数字孤独”。
    • 提升批判性思维与信息甄别能力： 帮助个体提升批判性思维和信息甄别能力，减少信息过载带来的负面影响。
    • 个性化干预： 考虑到不同个体对数字媒体的使用习惯和心理敏感性存在差异，未来的干预应更加注重个性化，根据个体的具体情况制定干预策略。

综上所述，数字时代的新兴挑战，如社交媒体的过度使用和电子屏幕时间的增加，通过多种心理和社会机制，如“数字孤独”、负面社会比较、信息过载和昼夜节律紊乱，增加了青少年和成年群体的抑郁风险。理解这些机制，并积极探索有效的数字健康干预和行为规范，对于维护数字时代的心理健康至关重要。

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参考文献

1Trends in Prevalent Cases and Disability-Adjusted Life-Years of Depressive Disorders Worldwide: Findings From the Global Burden of Disease Study From 1990 to 2021.PubMed

Xiao-Dan Chen, Feng Li, Hui Zuo, et al.
Depress Anxiety. 2025 Apr 24;2025:5553491. doi: 10.1155/da/5553491. eCollection 2025.
Depression is a primary public health challenge that affects individuals of all ages. This study aims to reveal information on spatial and temporal changes in depression by describing temporal trend differences, regional differences, and gender differences. Utilizing data from the Global Burden of Disease Study 2021 (GBD2021) from 1990 to 2021, we outlined the prevalence and burden of depression among 204 countries in 21 regions, including age and sex disparities, and explored the correlation between depressive burden and the sociodemographic index (SDI). The age-standardized rates of prevalence (ASPR), disability-adjusted life years (DALYs, age-standardized DALY rate, ASDR), and estimated annual percentage change (EAPC) were employed to evaluate the global burden of depression. Our study revealed a greater than 1.8-fold increase in prevalent cases and DALYs for global depressive disorder from 1990 to 2021. Globally, the age-standardized rates (ASRs) slightly declined, with a 1.32% decrease in the ASPR and a 1.84% decrease in the ASDR from 1990 to 2019. The main decline occurred from 2005 to 2010 (4.86% decrease in the ASPR and 6.09% decrease in the ASDR), with the majority of the contributions occurring in the low-middle-SDI and low-SDI regions. The global ASPR and ASDR experienced astonishing jumps from 2019 to 2021, resulting in increases of nearly 11% in the ASPR and 13% in the ASDR. Notably, the ASPR and ASDR of depression decreased in females but increased in males from 1990 to 2019 and reversed thereafter. From 1990 to 2021, among the 21 regions, the EAPCs in most regions were >0, with the only exceptional decline occurring in East Asia in the ASPR -0.06 [95% Cl:-0.10 to -0.03]) and ASDR -0.09 [95% Cl:-0.13 to -0.05]). Compared with those in other regions, the ASPR (0.42 [95% Cl: 0.34-0.49]) and ASDR (0.53 [95% Cl: 0.46-0.61]) were greater in high-income North America. Among the five SDI regions, the largest increases in ASPR (0.25 [95% Cl: 0.21-0.30]) and ASDR (0.31 [95% Cl: 0.26-0.37]) occurred in the high-SDI region, with the majority of the contributions occurring from 2019 to 2021. Worldwide, a decreasing trend and significant associations between the ASPR and the SDI ( = -0.22, =0.0013) and between the ASDR and the SDI ( = -0.28, < 0.001) were observed. Depression remains a serious challenge worldwide. The trends in depression burden varied across regions and groups. A vibrant socioeconomic environment could have a positive impact on the disease burden. Mental health should be incorporated into public health preparedness and emergency plans in practical ways on the basis of the national conditions of each country.

2The global, regional, and national late-life depression burden and trends from 1990 to 2021: A systematic analysis for the Global Burden of Disease Study 2021.PubMed

Quan Sun, Yulong Wei, Hongting Xie, et al.
Arch Gerontol Geriatr. 2025 Apr;131:105758. doi: 10.1016/j.archger.2025.105758. Epub 2025 Jan 13.
BACKGROUND: Late-life depression (LLD) represents a growing global public health concern. This study aimed to assess the worldwide burden of LLD using comprehensive data. METHODS: Leveraging the latest evidence from the Global Burden of Disease Study, we analyzed trends in LLD burden from 1990 to 2021, encompassing incidence, prevalence, and disability-adjusted life years (DALYs). We quantified disparities in LLD burden across socioeconomic, gender, regional, and national dimensions. Decomposition analysis was employed to identify key drivers of LLD burden variation. Frontier analysis illustrated the potential for burden reduction in various countries. RESULTS: Globally, there were 49,137,544 new cases, 46,672,175 prevalent cases, and 7,351,377 DALYs attributed to LLD in 2021. Between 1990 and 2021, the agestandardised incidence rate (ASIR), age-standardised prevalence rate (ASPR), and age-standardised DALYs rate (ASDR) of LLD all rose. In 2021, low SDI regions exhibited the highest all ASRs, while middle SDI regions had the fastest growth rates in these indicators. Regionally, Central and Eastern Sub-Saharan Africa had the highest ASIR, ASPR, and ASDR, respectively. Nationally, Uganda ranked highest in all ASRs in 2021. Women had higher burdens than men. Population growth was a primary driver of DALYs increase in middle SDI regions that had the greatest potential for improvement. CONCLUSIONS: The global burden of LLD has risen, with marked inequities across SDI, gender, region, and country. The burden is most pronounced in low and middle SDI regions. These findings offer guidance for developing LLD screening guidelines and enhancing prevention and intervention strategies in relevant countries, particularly Uganda.

3Sex Differences in Neuropsychiatric Symptoms in Alpha-Synucleinopathies: A Systematic Review and Meta-Analysis.PubMed

Vincent Couture, Jean-François Carmel, Katerine Rousseau, et al.
Mov Disord Clin Pract. 2024 Nov;11(11):1335-1344. doi: 10.1002/mdc3.14227. Epub 2024 Oct 9.
BACKGROUND: Alpha-synucleinopathies, such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB), demonstrate sex differences with regard to prevalence, age of onset, and motor manifestations. Neuropsychiatric symptoms (NPS) are common early and late manifestations of these disorders. OBJECTIVES: We aimed to describe sex differences in NPS across alpha-synucleinopathies. METHODS: We searched Web of Science Core collection databases to identify observational studies published between January 1, 2000, and June 1, 2022, reporting the prevalence or severity of NPS among individuals with a diagnosis of PD, PDD, or DLB. Prevalence and severity were pooled for each NPS according to sex using random-effects models. RESULTS: Two-hundred-and-forty studies, representing 796,026 participants (45% females), were included in the meta-analysis. Female sex was associated with a higher prevalence of anxiety (OR = 1.60 [95% CI: 1.40, 1.82]), depression (OR = 1.56 [1.45, 1.67]), fatigue (OR = 1.21 [1.02, 1.43]), and psychotic symptoms (OR = 1.26 [1.14, 1.40]) and more severe anxiety (g = 1.35 [95% CI: 0.58, 2.13]), depression (g = 1.57 [1.05, 2.08]), and fatigue (g = 0.86 [0.41, 1.32]), while male sex was associated with a higher prevalence of apathy (OR = 0.77 [0.63, 0.93]), impulse control disorders (OR = 0.67 [0.55, 0.82]), REM sleep behavior disorder (OR = 0.54 [0.42, 0.70]), hypersomnolence (OR = 0.67 [0.56, 0.80]), and suicide (OR = 0.30 [0.20, 0.44]). CONCLUSIONS: NPS have different prevalences and severities in alpha-synucleinopathies according to sex. These findings support consideration of sex in the elaboration of clinical tools.

4Global burden of depression or depressive symptoms in children and adolescents: A systematic review and meta-analysis.PubMed

Bingqing Lu, Lixia Lin, Xiaojuan Su
J Affect Disord. 2024 Jun 1;354:553-562. doi: 10.1016/j.jad.2024.03.074. Epub 2024 Mar 14.
BACKGROUND: Depression is the leading cause of health-related disability. A proportion of depression cases begin in childhood and increase dramatically during adolescence. This systematic review and meta-analysis aimed to estimate the global prevalence of depression or depressive symptoms in children and adolescents and explore the temporal and regional distribution of depression or depressive symptoms. METHODS: This systematic review and meta-analysis identified peer-reviewed literature published through April 8, 2023, using the MEDLINE, Embase and APA PsycINFO databases, supplemented by reverse reference searches. Observational studies published in English and based on validated instruments with prevalence data on depression or depressive symptoms in children and adolescents aged ≤18 years were eligible. Random-effects meta-analysis and meta-regression analysis were performed using R software. RESULTS: This systematic review and meta-analysis included a total of 96 studies (29 countries, 528,293 participants) published between 1989 and 2022. The pooled prevalence of mild-to-severe, moderate-to-severe, and major depression were 21.3 % (95%CI, 16.7 %-26.7 %), 18.9 % (95%CI, 14.6 %-24.2 %), and 3.7 % (95%CI, 2.7 %-5.1 %) respectively. Meta-regression analysis showed that from 1989 to 2022, the prevalence of mild-to-severe and moderate-to-severe depression increased over time (P = 0.002, P = 0.034, respectively), but the prevalence of major depression did not change significantly (P = 0.636). LIMITATIONS: Only English articles were included. There was significant heterogeneity across the included studies. The studies included were mostly based on self-report scales to assess depressive symptoms. CONCLUSION: In this systematic review, about one in five children and adolescents globally suffered from depression or had depressive symptoms, and this proportion was increasing over time.

5Global, regional and national burdens of major depression disorders and its attributable risk factors in adolescents and young adults aged 10-24 years from 1990 to 2021.PubMed

Yutong Zhang, Zeheng Li, Qian Feng, et al.
BMC Psychiatry. 2025 Apr 18;25(1):399. doi: 10.1186/s12888-025-06772-w.
BACKGROUND: Major depressive disorder (MDD) is an important public health problem among adolescents and young adults, and its increasing prevalence underscores the need for region-specific and age-specific interventions. Despite its increasing burden, comprehensive data on regional and longitudinal trends in MDD among adolescents are scarce. This study analyzed global, regional, and national trends in MDD incidence, prevalence, and disability-adjusted life years (DALYs) among individuals aged 10-24 from 1990 to 2021, while examining differences by gender, age, socio-demographic factors, and emerging risk factors to guide targeted mental health strategies. METHODS: With data from the 2021 Global Burden of Disease Study, we conducted an analysis of age-standardized incidence, prevalence, and DALYs due to MDD by sex, age group, and 21 geographic regions with a special focus on sociodemographic index (SDI) levels, which measures development on a scale from low to high. Key risk factors, such as bullying and intimate partner violence, were also assessed in order to understand their contribution to the burden of MDD. RESULTS: Between 1990 and 2021, the global burden of MDD increased substantially. Prevalence rose by 56.36% globally, particularly among men and young adults aged 20-24 years, with the largest increases observed in Eastern Sub-Saharan Africa (184.26% increase). Incidence grew by 56.11%, with Eastern Sub-Saharan Africa experiencing the steepest rise compared to slower increases in other regions. DALYs also increased by 56.32%, with the greatest burden observed in Eastern Sub-Saharan Africa. Bullying and intimate partner violence were leading contributors to DALYs across all regions. Bullying and childhood sexual abuse increased MDD-related DALYs, with bullying peaking at ages 10-14, while childhood sexual abuse had a higher impact on females, rising sharply after 2006. Post- 2020, all metrics (prevalence, incidence, and DALYs) rose sharply, particularly in high-SDI regions, likely due to the specific impacts of the COVID- 19 pandemic, such as prolonged lockdowns, increased social isolation, and disruptions to mental health services. CONCLUSIONS: This study highlights the need for culturally sensitive mental health policies focusing on prevention and early intervention, while also providing insights to improve resource allocation and support further research on adolescent mental health. TRIAL REGISTRATION: Not applicable.

6Global prevalence of depression, anxiety, and stress in the elderly population: a systematic review and meta-analysis.PubMed

Amir Jalali, Arash Ziapour, Zohreh Karimi, et al.
BMC Geriatr. 2024 Oct 4;24(1):809. doi: 10.1186/s12877-024-05311-8.
BACKGROUND: Several preliminary studies have been conducted in the field of the prevalence of depression, anxiety, and stress in the elderly population. These studies have examined the prevalence in limited geographic areas with small sample sizes. Also, there are many limitations in the meta-analysis studies. The objective of the present study was to synthesize the global prevalence statistics of depression, anxiety, and stress in the elderly population through a systematic review and meta-analysis. METHODS: The present systematic review included retrieval of primary studies from the oldest relevant study up to 2023. To find the relevant studies, international databases such as Scopus, Embase, PubMed, and Web of Science (WoS) were systematically searched. Also, a manual search was performed through the Google Scholar search engine and a review of the sources of related articles. The qualitative assessment of the studies was conducted using the Joanna Briggs Institute (JBI) checklist. Due to a high heterogeneity among the study results, a Random Effects model was chosen. RESULTS: A total of 42 articles on depression, 47 articles on anxiety and 13 articles on stress were included in the meta-analysis. The overall estimates for prevalence based on a random-effects model were as follows: depression, 19.2% (95% CI: 13.0 - 27.5%); anxiety, 16.5% (95% CI: 11.1 - 22.8%); and stress, 13.9% (95% CI: 5.5 - 30.9%). The highest prevalence of depression and anxiety was recorded in Africa. The prevalence of depression was higher in nursing homes, and stress was more prevalent in individuals with COVID-19 compared to other populations. CONCLUSION: The findings revealed a high prevalence of depression, anxiety, and stress in the elderly population. Therefore, it is recommended that healthcare professionals and policymakers pay more attention to the prevention and management of these disorders in the elderly population.

7Global, regional, and national burden of geriatric depressive disorders in people aged 60 years and older: an analysis of the Global Burden of Disease Study 2021.PubMed

Yuchang Fei, Huan Yu, Jiewen Liu, et al.
Ann Gen Psychiatry. 2025 Apr 5;24(1):22. doi: 10.1186/s12991-025-00560-2.
BACKGROUND: Late-life depression (LLD) stands as a prevalent mental health issue among older adults, frequently intertwined with cardiovascular and cerebrovascular diseases as well as cognitive decline. The occurrence of LLD in the older adults, who often present with multiple aging-related conditions, frequently results in this disorder being overlooked. However, the astronomical treatment costs and the considerable societal burden associated with LLD necessitate urgent and sustained attention. MATERIALS AND METHODS: Utilizing data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021), we extracted incidence rates and disability-adjusted life years (DALYs) of LLD in individuals aged 60 and older. The extracted data underwent rigorous evaluation through the application of age-period-cohort models, the health inequality concentration index, and frontier analysis. RESULTS: From 1990 to 2021, a global increase was observed in both the age-standardized incidence rate (ASIR) and DALY rate of LLD. Specifically, the ASIR ascended by 0.01 per 100,000 annually, while the DALY rate rose by 0.03 per 100,000 each year. Notably, a statistically significant inverse relationship was identified between ASIR and the Socio-demographic Index (SDI) (p < 0.001). Additionally, a notable linear correlation was discerned between age-standardized death rate (ASDR) and SDI, albeit without a discernible downward trend (p < 0.001). According to the SDI, the Estimated average percentage change (EAPC) of five SDI districts showed no increase or decrease. Globally, the incidence of LLD showed an upward trend in the high SDI, middle SDI, and low-middle SDI regions, a downward trend in the high-middle SDI region, and no significant increase or decrease in the low SDI region. In the age-period-cohort analysis, we found that the incidence of LLD increased with age in high and middle SDI regions compared with low SDI regions, and the results were the opposite in low SDI regions, with significant regional characteristics. The period effect analysis revealed that irrespective of gender, the trends in incidence and DALY rates remained relatively unchanged globally from 1992 to 2021. As SDI levels rose, the SDI-adjusted disparities in incidence and DALY rates tended to stabilize. A comparative analysis of data from 1990 to 2021 highlighted a relative decline in health inequalities. CONCLUSION: This comprehensive assessment of the disease burden of LLD among the global population aged 60 and older underscores significant accomplishments while simultaneously emphasizing areas requiring ongoing vigilance. In the context of relentless population growth and aging, the favorable downturns in incidence and DALY rates reflect tangible advancements in managing LLD.

8Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic.PubMed

Lancet. 2021 Nov 6;398(10312):1700-1712. doi: 10.1016/S0140-6736(21)02143-7. Epub 2021 Oct 8.
BACKGROUND: Before 2020, mental disorders were leading causes of the global health-related burden, with depressive and anxiety disorders being leading contributors to this burden. The emergence of the COVID-19 pandemic has created an environment where many determinants of poor mental health are exacerbated. The need for up-to-date information on the mental health impacts of COVID-19 in a way that informs health system responses is imperative. In this study, we aimed to quantify the impact of the COVID-19 pandemic on the prevalence and burden of major depressive disorder and anxiety disorders globally in 2020. METHODS: We conducted a systematic review of data reporting the prevalence of major depressive disorder and anxiety disorders during the COVID-19 pandemic and published between Jan 1, 2020, and Jan 29, 2021. We searched PubMed, Google Scholar, preprint servers, grey literature sources, and consulted experts. Eligible studies reported prevalence of depressive or anxiety disorders that were representative of the general population during the COVID-19 pandemic and had a pre-pandemic baseline. We used the assembled data in a meta-regression to estimate change in the prevalence of major depressive disorder and anxiety disorders between pre-pandemic and mid-pandemic (using periods as defined by each study) via COVID-19 impact indicators (human mobility, daily SARS-CoV-2 infection rate, and daily excess mortality rate). We then used this model to estimate the change from pre-pandemic prevalence (estimated using Disease Modelling Meta-Regression version 2.1 [known as DisMod-MR 2.1]) by age, sex, and location. We used final prevalence estimates and disability weights to estimate years lived with disability and disability-adjusted life-years (DALYs) for major depressive disorder and anxiety disorders. FINDINGS: We identified 5683 unique data sources, of which 48 met inclusion criteria (46 studies met criteria for major depressive disorder and 27 for anxiety disorders). Two COVID-19 impact indicators, specifically daily SARS-CoV-2 infection rates and reductions in human mobility, were associated with increased prevalence of major depressive disorder (regression coefficient [B] 0·9 [95% uncertainty interval 0·1 to 1·8; p=0·029] for human mobility, 18·1 [7·9 to 28·3; p=0·0005] for daily SARS-CoV-2 infection) and anxiety disorders (0·9 [0·1 to 1·7; p=0·022] and 13·8 [10·7 to 17·0; p<0·0001]. Females were affected more by the pandemic than males (B 0·1 [0·1 to 0·2; p=0·0001] for major depressive disorder, 0·1 [0·1 to 0·2; p=0·0001] for anxiety disorders) and younger age groups were more affected than older age groups (-0·007 [-0·009 to -0·006; p=0·0001] for major depressive disorder, -0·003 [-0·005 to -0·002; p=0·0001] for anxiety disorders). We estimated that the locations hit hardest by the pandemic in 2020, as measured with decreased human mobility and daily SARS-CoV-2 infection rate, had the greatest increases in prevalence of major depressive disorder and anxiety disorders. We estimated an additional 53·2 million (44·8 to 62·9) cases of major depressive disorder globally (an increase of 27·6% [25·1 to 30·3]) due to the COVID-19 pandemic, such that the total prevalence was 3152·9 cases (2722·5 to 3654·5) per 100 000 population. We also estimated an additional 76·2 million (64·3 to 90·6) cases of anxiety disorders globally (an increase of 25·6% [23·2 to 28·0]), such that the total prevalence was 4802·4 cases (4108·2 to 5588·6) per 100 000 population. Altogether, major depressive disorder caused 49·4 million (33·6 to 68·7) DALYs and anxiety disorders caused 44·5 million (30·2 to 62·5) DALYs globally in 2020. INTERPRETATION: This pandemic has created an increased urgency to strengthen mental health systems in most countries. Mitigation strategies could incorporate ways to promote mental wellbeing and target determinants of poor mental health and interventions to treat those with a mental disorder. Taking no action to address the burden of major depressive disorder and anxiety disorders should not be an option. FUNDING: Queensland Health, National Health and Medical Research Council, and the Bill and Melinda Gates Foundation.

9Global Prevalence of Depressive and Anxiety Symptoms in Children and Adolescents During COVID-19: A Meta-analysis.PubMed

Nicole Racine, Brae Anne McArthur, Jessica E Cooke, et al.
JAMA Pediatr. 2021 Nov 1;175(11):1142-1150. doi: 10.1001/jamapediatrics.2021.2482.
IMPORTANCE: Emerging research suggests that the global prevalence of child and adolescent mental illness has increased considerably during COVID-19. However, substantial variability in prevalence rates have been reported across the literature. OBJECTIVE: To ascertain more precise estimates of the global prevalence of child and adolescent clinically elevated depression and anxiety symptoms during COVID-19; to compare these rates with prepandemic estimates; and to examine whether demographic (eg, age, sex), geographical (ie, global region), or methodological (eg, pandemic data collection time point, informant of mental illness, study quality) factors explained variation in prevalence rates across studies. DATA SOURCES: Four databases were searched (PsycInfo, Embase, MEDLINE, and Cochrane Central Register of Controlled Trials) from January 1, 2020, to February 16, 2021, and unpublished studies were searched in PsycArXiv on March 8, 2021, for studies reporting on child/adolescent depression and anxiety symptoms. The search strategy combined search terms from 3 themes: (1) mental illness (including depression and anxiety), (2) COVID-19, and (3) children and adolescents (age ≤18 years). For PsycArXiv, the key terms COVID-19, mental health, and child/adolescent were used. STUDY SELECTION: Studies were included if they were published in English, had quantitative data, and reported prevalence of clinically elevated depression or anxiety in youth (age ≤18 years). DATA EXTRACTION AND SYNTHESIS: A total of 3094 nonduplicate titles/abstracts were retrieved, and 136 full-text articles were reviewed. Data were analyzed from March 8 to 22, 2021. MAIN OUTCOMES AND MEASURES: Prevalence rates of clinically elevated depression and anxiety symptoms in youth. RESULTS: Random-effect meta-analyses were conducted. Twenty-nine studies including 80 879 participants met full inclusion criteria. Pooled prevalence estimates of clinically elevated depression and anxiety symptoms were 25.2% (95% CI, 21.2%-29.7%) and 20.5% (95% CI, 17.2%-24.4%), respectively. Moderator analyses revealed that the prevalence of clinically elevated depression and anxiety symptoms were higher in studies collected later in the pandemic and in girls. Depression symptoms were higher in older children. CONCLUSIONS AND RELEVANCE: Pooled estimates obtained in the first year of the COVID-19 pandemic suggest that 1 in 4 youth globally are experiencing clinically elevated depression symptoms, while 1 in 5 youth are experiencing clinically elevated anxiety symptoms. These pooled estimates, which increased over time, are double of prepandemic estimates. An influx of mental health care utilization is expected, and allocation of resources to address child and adolescent mental health concerns are essential.

10Prevalence and associated factors of depression and anxiety symptoms among college students: a systematic review and meta-analysis.PubMed

Wenzhen Li, Zhiya Zhao, Dajie Chen, et al.
J Child Psychol Psychiatry. 2022 Nov;63(11):1222-1230. doi: 10.1111/jcpp.13606. Epub 2022 Mar 16.
BACKGROUND: To evaluate the global prevalence of depression and anxiety symptoms among college students and potential associated factors. METHODS: PubMed and Web of Science were searched from their inception to March 28, 2021. Random-effects models were used to calculate the pooled prevalence of depression and anxiety. Subgroup analyses were conducted to explore potential heterogeneity. Egger's and Begg's test were used to assess publication bias. RESULTS: A total of 64 studies with 100,187 individuals were included in the present meta-analysis. The pooled prevalence of depression and anxiety symptoms among college students was 33.6% (95% confidence interval [CI] 29.3%-37.8%) and 39.0% (95% CI, 34.6%-43.4%), respectively. The highest prevalence of depression symptoms was found in Africa region (40.1%, 95% CI 12.3-67.9%), lower middle-income countries (42.5%, 95% CI 28.6-56.3%), and medical college students (39.4%, 95% CI 29.3-49.6%). For the prevalence of anxiety symptoms, the highest was observed in North America (48.3%, 95% CI 37.4-59.2%), lower middle-income countries (54.2%, 95% CI 35.0-73.4%), medical college students (47.1%, 95% CI 35.1-59.1%) and identified by Beck Anxiety Inventory (BAI) (49.1%, 95% CI 31.0-43.0%). Besides, the prevalence of depression symptoms (35.9%, 95% CI 20.2-51.7%) and anxiety symptoms (40.7%, 95% CI 39.5-42.0%) was higher in studies conducted after the coronavirus disease 2019 (COVID-19) outbreak. CONCLUSIONS: Our study suggests that a lot of college students experience depression and anxiety symptoms and clarifies factors that are related to these mental disorders. Effective prevention and intervention strategies for mental disorders should be developed among college students.

11Prevalence of depressive disorders and treatment in China: a cross-sectional epidemiological study.PubMed

Jin Lu, Xiufeng Xu, Yueqin Huang, et al.
Lancet Psychiatry. 2021 Nov;8(11):981-990. doi: 10.1016/S2215-0366(21)00251-0. Epub 2021 Sep 21.
BACKGROUND: In China, depressive disorders have been estimated to be the second leading cause of years lived with disability. However, nationally representative epidemiological data for depressive disorders, in particular use of mental health services by adults with these disorders, are unavailable in China. The present study, part of the China Mental Health Survey, 2012-15, aims to describe the socioeconomic characteristics and the use of mental health services in people with depressive disorders in China. METHODS: The China Mental Health Survey was a cross-sectional epidemiological survey of mental disorders in a multistage clustered-area probability sample of adults of Chinese nationality (≥18 years) from 157 nationwide representative population-based disease surveillance points in 31 provinces across China. Trained investigators interviewed the participants with the Composite International Diagnostic Interview 3.0 to ascertain the presence of lifetime and 12-month depressive disorders according to DSM-IV criteria, including major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Participants with 12-month depressive disorders were asked whether they received any treatment for their emotional problems during the past 12 months and, if so, the specific types of treatment providers. The Sheehan Disability Scale (SDS) was used to assess impairments associated with 12-month depressive symptoms. Data-quality control procedures included logic check by computers, sequential recording check, and phone-call check by the quality controllers, and reinterview check by the psychiatrists. Data were weighted according to the age-sex-residence distribution data from China's 2010 census population survey to adjust for differential probabilities of selection and differential response, as well as to post-stratify the sample to match the population distribution. FINDINGS: 28 140 respondents (12 537 [44·6%] men and 15 603 [55·4%] women) completed the survey between July 22, 2013, and March 5, 2015. Ethnicity data (Han or non-Han) were collected for only a subsample. Prevalence of any depressive disorders was higher in women than men (lifetime prevalence odds ratio [OR] 1·44 [95% CI 1·20-1·72] and 12-month prevalence OR 1·41 [1·12-1·78]), in unemployed people than employed people (lifetime OR 2·38 [95% CI 1·68-3·38] and 12-month OR 2·80 [95% CI 1·88-4·18]), and in people who were separated, widowed, or divorced compared with those who were married or cohabiting (lifetime OR 1·87 [95% CI 1·39-2·51] and 12-month OR 1·85 [95% CI 1·40-2·46]). Overall, 574 (weighted % 75·9%) of 744 people with 12-month depressive disorders had role impairment of any SDS domain: 439 (83·6%) of 534 respondents with major depressive disorder, 207 (79·8%) of 254 respondents with dysthymic disorder, and 122 (59·9%) of 189 respondents with depressive disorder not otherwise specified. Only an estimated 84 (weighted % 9·5%) of 1007 participants with 12-month depressive disorders were treated in any treatment sector: 38 (3·6%) in speciality mental health, 20 (1·5%) in general medical, two (0·3%) in human services, and 21 (2·7%) in complementary and alternative medicine. Only 12 (0·5%) of 1007 participants with depressive disorders were treated adequately. INTERPRETATION: Depressive disorders in China were more prevalent in women than men, unemployed people than employed, and those who were separated, widowed, or divorced than people who were married or cohabiting. Most people with depressive disorders reported social impairment. Treatment rates were very low, and few people received adequate treatment. National programmes are needed to remove barriers to availability, accessibility, and acceptability of care for depression in China. FUNDING: National Health Commission and Ministry of Science and Technology of People's Republic of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

12Association of Depression With All-Cause and Cardiovascular Disease Mortality Among Adults in China.PubMed

Ruiwei Meng, Canqing Yu, Na Liu, et al.
JAMA Netw Open. 2020 Feb 5;3(2):e1921043. doi: 10.1001/jamanetworkopen.2019.21043.
IMPORTANCE: Depression is associated with increased disease burden worldwide and with higher risk of mortality in Western populations. OBJECTIVE: To investigate whether depression is a risk factor for all-cause and cardiovascular disease (CVD) mortality in adults in China. DESIGN, SETTING, AND PARTICIPANTS: This cohort study prospectively followed adults aged 30 to 79 years in the China Kadoorie Biobank (CKB) study from June 1, 2004, to December 31, 2016, and adults aged 32 to 104 years in the Dongfeng-Tongji (DFTJ) study from September 1, 2008, to December 31, 2016. Data analysis was conducted from June 1, 2018, to March 31, 2019. MAIN OUTCOMES AND MEASURES: Depression was evaluated using the Chinese version of the World Health Organization Composite International Diagnostic Interview-Short Form in the CKB cohort and a 7-item symptoms questionnaire modified from the Composite International Diagnostic Interview-Short Form in the DFTJ cohort. Multivariable-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for the association of depression with mortality. Covariates in the final models included sociodemographic characteristics, lifestyle factors, and personal and family medical history. RESULTS: Among 512 712 individuals (mean [SD] age, 52.0 [10.7] years; 302 509 [59.0%] women) in the CKB cohort, there were 44 065 deaths, including 18 273 CVD deaths. The 12-month prevalence of major depressive episode in the CKB cohort was 0.64%, and the 1-month prevalence of clinically significant depressive symptoms was 17.96% in the DFTJ cohort. Among 26 298 individuals (mean [SD] age, 63.6 [7.8] years; 14 508 [55.2%] women) in the DFTJ cohort, there were 2571 deaths, including 1013 CVD deaths. In the multivariable-adjusted model, depression was associated with increased risk of all-cause mortality (CKB cohort: HR, 1.32 [95% CI, 1.20-1.46]; P < .001; DFTJ cohort: HR, 1.17 [95% CI, 1.06-1.29]; P = .002) and CVD mortality (CKB cohort: HR, 1.22 [95% CI, 1.04-1.44]; P = .02; DFTJ cohort: HR, 1.32 [95% CI, 1.14-1.54]; P < .001). In both cohorts, men had statistically significantly higher risk of all-cause mortality (CKB cohort: HR, 1.53 [95% CI, 1.32-1.76]; DFTJ cohort: HR, 1.24 [95% CI, 1.10-1.41]) and CVD mortality (CKB cohort: HR, 1.39 [95% CI, 1.10-1.76]; DFTJ cohort: HR, 1.49 [95% CI, 1.23-1.80]), while the association of depression with mortality among women was only significant for all-cause mortality in the CKB cohort (HR, 1.19 [95% CI, 1.03-1.37]). CONCLUSIONS AND RELEVANCE: These findings suggest that depression is associated with an increased risk of all-cause and CVD mortality in adults in China, particularly in men. These findings highlight the importance and urgency of depression management as a measure for preventing premature deaths in China.

13Association of Depressive Symptoms With Incident Cardiovascular Diseases in Middle-Aged and Older Chinese Adults.PubMed

Haibin Li, Deqiang Zheng, Zhiwei Li, et al.
JAMA Netw Open. 2019 Dec 2;2(12):e1916591. doi: 10.1001/jamanetworkopen.2019.16591.
IMPORTANCE: The prevalence of depressive symptoms among older adults has become an increasingly important public health priority. Elevated depressive symptoms are well documented among elderly people with cardiovascular disease (CVD), but studies conducted among Chinese adults are scarce. OBJECTIVE: To estimate the association between depressive symptoms and incident CVD among middle-aged and older Chinese adults. DESIGN, SETTING, AND PARTICIPANTS: The China Health and Retirement Longitudinal Study is an ongoing nationally representative prospective cohort study that was initiated in 2011. This cohort study included 12 417 middle-aged and older Chinese adults without heart disease and stroke at baseline. Statistical analysis was conducted from April 25, 2018, to December 13, 2018. EXPOSURE: Depressive symptoms were assessed using the validated 10-item of Center for Epidemiologic Studies Depression Scale. MAIN OUTCOMES AND MEASURES: Incident CVD (ie, self-reported physician-diagnosed heart disease and stroke combined) was followed-up from June 1, 2011, to June 31, 2015. The Center for Epidemiologic Studies Depression Scale total score ranges from 0 to 30, with a score of 12 or more indicating elevated depressive symptoms. RESULTS: Of the 12 417 participants (mean [SD] age at baseline, 58.40 [9.51] years), 6113 (49.2%) were men. During the 4 years of follow-up, 1088 incident CVD cases were identified. Elevated depressive symptoms were independently associated with an increased CVD risk (adjusted hazard ratio, 1.39; 95% CI, 1.22-1.58) after adjusting for age, sex, residence, marital status, educational level, smoking status, drinking status, systolic blood pressure, and body mass index; history of diabetes, hypertension, dyslipidemia, and chronic kidney disease; and use of hypertension medications, diabetes medications, and lipid-lowering therapy. Of the 10 individual depressive symptoms measured by the Center for Epidemiologic Studies Depression Scale, only 2 symptoms, restless sleep (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.39) and loneliness (adjusted hazard ratio, 1.21; 95% CI, 1.02-1.44), were significantly associated with incident CVD. CONCLUSIONS AND RELEVANCE: Elevated depressive symptoms overall and 2 individual symptoms (restless sleep and loneliness) were significantly associated with incident CVD among middle-aged and older Chinese adults.

14Obesity and the onset of depressive symptoms among middle-aged and older adults in China: evidence from the CHARLS.PubMed

Huiqiang Luo, Jijie Li, Qi Zhang, et al.
BMC Public Health. 2018 Jul 24;18(1):909. doi: 10.1186/s12889-018-5834-6.
BACKGROUND: The association between obesity and depression has been documented in previous systematic studies but remains controversial. Many prospective studies have focused on children and youth, and several studies have examined this relationship among older populations. This study of the changes in obesity status aimed to examine the association between depression and obesity among middle-aged and elderly adults in China. METHODS: The data originated from the follow-up survey (2011 and 2013-2015) of the China Health and Retirement Longitudinal Study (CHARLS) and included 3337 residents aged at least 45 years who completed a physical examination and were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D-10), which assessed depressive symptoms. Obesity status was defined by body mass index (BMI) and waist circumference (WC) according to Chinese criteria. A time-dependent Cox proportional hazards model was used to estimate the relationship between obesity status and depressive symptoms. RESULTS: The rate of depression in men and women was 26.67 and 38.37%, respectively. Based on BMI, the proportion of the population that was overweight and obese was 28.07 and 9.26%, respectively, in males and 35.03 and 16.84%, respectively, in females. Males with obesity were less likely to suffer from depressive symptoms than males with a normal weight (ORHR = 0.506, 95% CI = 0.347~ 0.736). Based on WC, the proportion of abdominal obesity was 49.35% in males and 73.65% in females. Males with abdominal obesity were less likely to suffer from depressive symptoms than males without abdominal obesity (ORHR = 0.775, 95% CI = 0.644~ 0.933). CONCLUSION: Obesity is more likely to be associated with the onset of depression in males than in females. However, regardless of underweight or overweight status, the relationship between weight and depressive symptoms is negatively associated among females and males. In conclusion, both BMI and WC can be used as tools for examining the association between obesity and depression.

15Development and validation of a depression risk prediction model for rural elderly living alone.PubMed

Shasha Gao, Huijun Zhang
BMC Psychiatry. 2025 Apr 9;25(1):357. doi: 10.1186/s12888-025-06785-5.
BACKGROUND: Depression is a prevalent psychological issue among rural elderly individuals living alone, severely impacting their physical and mental health. OBJECTIVE: To develop and validate a depression risk prediction model for rural elderly living alone based on the health ecological model, providing a scientific basis for early intervention. METHODS: Using data from the 2011 China Health and Retirement Longitudinal Study (CHARLS), we included 1,221 participants. Thedataset was randomly stratified into a training set (70%) and a validation set (30%). Predictors were screened via univariate analysis, followed by multivariate logistic regression to construct the nomogram model. Statistical analysis was performed using R Studio 4.4.1.Ten-fold cross-validation was used to assess the model's stability. Model performance was evaluated using the Receiver Operating Characteristic (ROC) curve, with the Area Under the Curve (AUC) calculated, along with calibration plots, the Hosmer-Lemeshow test, and Decision Curve Analysis (DCA). RESULTS: Self-rated health, pain, frailty, nighttime sleep duration, poor sleep quality, life satisfaction, and visit frequency were identified as independent predictors of depressive symptoms. The model demonstrated excellent discrimination (AUC = 0.85 [95% CI: 0.83-0.88] in the training set and 0.83 [95% CI: 0.78-0.87] in validation), good calibration (Hosmer-Lemeshow test p = 0.47), and high clinical utility (net benefit > 10% in DCA). CONCLUSION: The nomogram provides a reliable and intuitive tool for early screening of depressive symptoms in rural elderly individuals living alone, supporting targeted interventions. CLINICAL TRIAL NUMBER: Not applicable.

16Risk prediction models of depression in older adults with chronic diseases.PubMed

Ying Zheng, Chu Zhang, Yuwen Liu
J Affect Disord. 2024 Aug 15;359:182-188. doi: 10.1016/j.jad.2024.05.078. Epub 2024 May 18.
BACKGROUND: Detecting potential depression and identifying the critical predictors of depression among older adults with chronic diseases are essential for timely intervention and management of depression. Therefore, risk prediction models (RPMs) of depression in elderly people should be further explored. METHODS: A total of 3959 respondents aged 60 years or over from the wave four survey of the China Health and Retired Longitudinal Study (CHARLS) were included in this study. We used five machine learning (ML) algorithms and three data balancing techniques to construct RPMs of depression and calculated feature importance scores to determine which features are essential to depression. RESULTS: The prevalence of depression was 19.2 % among older Chinese adults with chronic diseases in the wave four survey. The random forest (RF) model was more accurate than the other models after balancing the data using the Synthetic Minority Oversampling Technique (SMOTE) algorithm, with an area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC) of 0.957 and 0.920, respectively, a balanced accuracy of 0.891 and a sensitivity of 0.875. Furthermore, we further identified several important predictors between male and female patients via constructed sex-stratified models. LIMITATIONS: Further research on the clinical impact studies of our models and external validation are needed. CONCLUSIONS: After several techniques were used to address class imbalance issues, most RPMs achieved satisfactory accuracy in predicting depression among elderly people with chronic diseases. RPMs may thus become valuable screening tools for both older individuals and healthcare practitioners to assess the risk of depression.

17The Factors of Adolescent Depression in Jiangsu Province, China, from the Perspective of Social Ecosystem: A Case-Control Study.PubMed

Hua Xu, Zhao-Hong Chen, Jin-Jie Ji, et al.
Depress Anxiety. 2023 Nov 11;2023:2861629. doi: 10.1155/2023/2861629. eCollection 2023.
BACKGROUND: The prevalence of adolescent depression is continuously increasing, impacting the cognitive, emotional, and behavioral development of adolescents. Therefore, it is crucial to comprehend depression from the perspective of the social ecosystem, necessitating further empirical evaluation. METHODS: This study utilized a case-control study design. The cases consisted of adolescents with depression (aged 13-18 years) admitted to a psychiatric hospital in Nanjing, Jiangsu Province, China, from November 2021 to July 2022, meeting the diagnostic criteria for depression in the 11th Edition of the International Classification of Diseases. Control group students, with a matching gender ratio in the same region, were randomly recruited. Logistic regression analysis was employed to investigate the factors associated with depression, with gender and age as covariates. RESULTS: The study comprised 200 participants, with 44 (22.0%) males and 156 (78.0%) females. Multiple logistic regression analysis revealed that increased adolescent depression was associated with being an only child (AOR = 2.680, 95% CI: 1.106-6.492), living in urban areas (AOR = 3.324, 95% CI: 1.077-10.267), experiencing school bullying (AOR = 9.087, 95% CI: 2.044-40.408), having severe family dysfunction (AOR = 6.491, 95% CI: 1.109-37.995), and possessing low core self-evaluation (AOR = 11.746, 95% CI: 3.305-41.746). Odds ratios for each factor were statistically significant. CONCLUSIONS: Our results improve the evidence for associations between adolescent depression and core self-evaluation, school bullying, family function, living in urban areas, and being an only child. These findings should be taken into consideration in the assessment, intervention, and related policies for adolescent depression.

18Gender differences in depression, anxiety, and stress among college students: A longitudinal study from China.PubMed

Wenjuan Gao, Siqing Ping, Xinqiao Liu
J Affect Disord. 2020 Feb 15;263:292-300. doi: 10.1016/j.jad.2019.11.121. Epub 2019 Dec 4.
BACKGROUND: The objective of this longitudinal study was to examine the gender differences in college students' depression, anxiety, and stress over the four academic years, and to explore possible anxiety-related factors among first year students. METHODS: The study analyzed 1892 undergraduate students from 15 universities in China, with 898 females and 994 males. The students have been followed for four years and completed a survey containing the Depression Anxiety Stress Scale-21 questionnaire, students' socio-demographic information, and their educational background, etc. RESULTS: (1) On average, both female and male college students suffered from mild anxiety in the first three years. Female students scored significantly higher in anxiety than males in the first and second years, and there was no significant gender difference in students' average depression and stress levels. (2) A significantly larger proportion of female students experienced anxiety above the normal threshold, whereas a higher percentage of male students endured different degrees of depression; no significant gender differences were found in stress problems. (3) Anxiety had a significant positive correlation with introversion. Female freshmen's anxiety levels were also associated with their body image, drinking habits, and academic performance. LIMITATIONS: Response bias may exist considering that self-reported data was used. Due to data unavailability, we only explored the anxiety-related factors in freshman year, which cannot sufficiently reflect the consistency of correlations over time. CONCLUSIONS: Anxiety turned out to be the most prevalent and serious issue for college students, especially for female students; while a growing prevalence of depression was found among male students during college. It is of great significance to adopt collegiate policies reflecting the gender differentials.

19Urban-Rural Differences in Older Adult Depression: A Systematic Review and Meta-analysis of Comparative Studies.PubMed

Jonathan Purtle, Katherine L Nelson, Yong Yang, et al.
Am J Prev Med. 2019 Apr;56(4):603-613. doi: 10.1016/j.amepre.2018.11.008. Epub 2019 Feb 16.
CONTEXT: Depression among older adults (aged 60 years or older) is a problem that could be exacerbated by global trends in urbanization and population aging. The study purpose was to assess whether urban, relative to rural, residence is associated with depression among older adults and whether associations differ in countries with developed versus developing economies. EVIDENCE ACQUISITION: In 2017, the authors identified and extracted information from comparative studies of urban-rural depression prevalence among older adults. Studies were identified in PubMed, PsychINFO, and Web of Science and limited to English language articles published after 1985. Eighteen studies met inclusion criteria. Random effects meta-analysis was conducted to produce weighted pooled ORs estimating the association between urban-rural residence and depression for all study participants (N=31,598) and sub-analyses were conducted for developed (n=12,728) and developing (n=18,870) countries. EVIDENCE SYNTHESIS: Depression prevalence was significantly higher among urban residents in ten studies and significantly higher among rural residents in three studies (all three conducted in China). Associations between urban-rural residence and depression generally remained significant after adjusting for covariates. In developed countries, the odds of depression were significantly higher among urban than rural residents (pooled OR=1.44, 95% CI=1.10, 1.88). However, in developing countries, this association was not observed (pooled OR=0.91, 95% CI=0.46, 1.77). CONCLUSIONS: Converging trends of urbanization and population aging could increase the global burden of depression among older adults. The pathways through which urban-rural residence influences depression risk among older adults might differ by country context. Future research should focus on measuring variation in these contexts.

20Predicting depression among rural and urban disabled elderly in China using a random forest classifier.PubMed

Yu Xin, Xiaohui Ren
BMC Psychiatry. 2022 Feb 15;22(1):118. doi: 10.1186/s12888-022-03742-4.
With global aging, the number of elderly with physical disabilities is also increasing. Compared with the ordinary elderly, the elderly who lose their independence are more likely to have the symptoms of depression. Reducing depression may help to alleviate the disability process of those who find themselves in the disabled stages. Therefore, the purpose of this study is to explore the predictive effects of demographic characteristics, health behavior, health status, family relations, social relations, and subjective attitude on depression in rural and urban disabled elderly to improve early depression symptom recognition.A total of 1460 older adults aged 60 and disabled were selected from China Family Panel Studies (CFPS). Depression was assessed according to The Center for Epidemiologic Studies Depression Scale (CES-D). This paper used the random forest classifier to predict the depression of the disabled elderly from six aspects: demographic characteristics, health status, health behavior, family relationship, and social relationship. The prediction model was established based on 70% of the training set and 30% of the test set. The depression rate of rural disabled elderly was 57.67%, and that of urban disabled elderly was 44.59%. The mean values of the 10-k cross-validated results were 0.71 in rural areas and 0.70 in urban areas. AUC:0.71, specificity: 65.3%, sensitivity: 80.6% for rural disabled elderly with depression; AUC:0.78, specificity: 78.1%, sensitivity: 64.2% for urban disabled elderly with depression, respectively. There are apparent differences in the top ten predictors between rural and urban disabled elderly. The common predictors were self-rated health, changing in perceived health, disease or accidence experience within the past 2 weeks, life satisfaction, trusting people, BMI, and having trust in the future. Non-common predictors were chronic diseases, neighborly relations, total medical expenses within 1 year, community emotion, sleep duration, and family per capita income. Using random forest data to predict the depression of the disabled elderly may lead to early detection of depression.

21Population-attributable fractions of risk factors for all-cause dementia in China rural and urban areas: a cross-sectional study.PubMed

Fei-Fei Hu, Gui-Rong Cheng, Dan Liu, et al.
J Neurol. 2022 Jun;269(6):3147-3158. doi: 10.1007/s00415-021-10886-y. Epub 2021 Nov 28.
BACKGROUND: The prevalence of dementia in China, particularly in rural areas, is consistently increasing; however, research on population-attributable fractions (PAFs) of risk factors for dementia is scarce. METHODS: We conducted a cross-sectional survey, namely, the China Multicentre Dementia Survey (CMDS) in selected rural and urban areas from 2018 to 2020. We performed face-to-face interviews and neuropsychological and clinical assessments to reach a consensus on dementia diagnosis. Prevalence and weighted PAFs of eight modifiable risk factors (six classical: less childhood education, hearing impairment, depression, physical inactivity, diabetes, and social isolation, and two novels: olfactory decline and being unmarried) for all-cause dementia were estimated. RESULTS: Overall, CMDS included 17,589 respondents aged ≥ 65 years, 55.6% of whom were rural residents. The age- and sex-adjusted prevalence for all-cause dementia was 9.11% (95% CI 8.96-9.26), 5.19% (5.07-5.31), and 11.98% (11.8-12.15) in the whole, urban, and rural areas of China, respectively. Further, the overall weighted PAFs of the eight potentially modifiable risk factors were 53.72% (95% CI 52.73-54.71), 50.64% (49.4-51.89), and 56.54% (55.62-57.46) in the whole, urban, and rural areas of China, respectively. The eight risk factors' prevalence differed between rural and urban areas. Lower childhood education (PAF: 13.92%) and physical inactivity (16.99%) were primary risk factors in rural and urban areas, respectively. CONCLUSIONS: The substantial urban-rural disparities in the prevalence of dementia and its risk factors exist, suggesting the requirement of resident-specific dementia-prevention strategies.

22Gender differences in rural-urban migration and its impact on depression in later life.PubMed

Jingwen Zhang, James Nazroo, Nan Zhang
Health Place. 2022 Sep;77:102890. doi: 10.1016/j.healthplace.2022.102890. Epub 2022 Aug 22.
Although rural-to-urban migration has been well researched, how gender shapes processes and outcomes, including later-life health outcomes, has not been thoroughly investigated. Guided by a life course perspective, this study explores gender differences in rural-urban migration patterns and its association with depression in later life among Chinese older adults. Exploiting rich life history data from the China Health and Retirement Longitudinal Study, we employ sequence analysis to identify the typical migration trajectories of Chinese older adults. Moderated mediation analysis is then used to examine gender-specific health pathways linking migration trajectories and later-life depression. The results indicate that: rural migrants who settled in urban regions have lower level of depression in later life than 'return migrants' who moved back to rural areas or those who were rural non-migrants; the gender gap in depression is marginally smaller among early urban settlers than rural non-migrants; and household income in later life has stronger mediation effects for migrant men than for migrant women. The study therefore highlights the importance of considering the role of gender when designing policies aiming to improve the health and wellbeing of migrants in later life.

23Global, regional and national burdens of depression in adolescents and young adults aged 10-24 years, from 1990 to 2019: findings from the 2019 Global Burden of Disease study.PubMed

Cheng-Hao Yang, Jia-Jie Lv, Xiang-Meng Kong, et al.
Br J Psychiatry. 2024 Aug;225(2):311-320. doi: 10.1192/bjp.2024.69.
BACKGROUND: Depression is a significant mental health concern affecting the overall well-being of adolescents and young adults. Recently, the prevalence of depression has increased among young people. Nonetheless, there is little research delving into the longitudinal epidemiology of adolescent depression over time. AIMS: To investigate the longitudinal epidemiology of depression among adolescents and young adults aged 10-24 years. METHOD: Our research focused on young people (aged 10-24 years) with depression, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. We explored the age-standardised prevalence, incidence and disability-adjusted life-years (DALYs) of depression in different groups, including various regions, ages, genders and sociodemographic indices, from 1990 to 2019. RESULTS: The prevalence, incidence and DALYs of depression in young people increased globally between 1990 and 2019. Regionally, higher-income regions like High-Income North America and Australasia recorded rising age-standardised prevalence and incidence rates, whereas low- or middle-income regions mostly saw reductions. Nationally, countries such as Greenland, the USA and Palestine reported the highest age-standardised prevalence and incidence rates in 2019, whereas Qatar witnessed the largest growth over time. The burden disproportionately affected females across age groups and world regions. The most prominent age effect on incidence and prevalence rates was in those aged 20-24 years. The depression burden showed an unfavourable trend in younger cohorts born after 1980, with females reporting a higher cohort risk than males. CONCLUSIONS: Between 1990 and 2019, the general pattern of depression among adolescents varied according to age, gender, time period and generational cohort, across regions and nations.

24Prevalence of mental disorders in school children and adolescents in China: diagnostic data from detailed clinical assessments of 17,524 individuals.PubMed

Fenghua Li, Yonghua Cui, Ying Li, et al.
J Child Psychol Psychiatry. 2022 Jan;63(1):34-46. doi: 10.1111/jcpp.13445. Epub 2021 May 21.
BACKGROUND: To date, no national-scale psychiatric epidemiological survey for children and adolescents has been conducted in China. In order to inform government officials and policymakers and to develop a comprehensive plan for service providers, there was a clear need to conduct an up-to-date systematic nationwide psychiatric epidemiological survey. METHODS: We conducted a two-stage large-scale psychiatric point prevalence survey. Multistage cluster stratified random sampling was used as the sampling strategy. Five provinces were selected by comprehensively considering geographical partition, economic development, and rural/urban factors. In Stage 1, the Child Behavior Checklist was used as the screening tool. In Stage 2, Mini-International Neuropsychiatric Interview for Children and Adolescents and a diagnostic process based on the Diagnostic and Statistical Manual were used to make the diagnoses. Sampling weights and poststratification weights were employed to match the population distributions. Exploratory analyses were also performed using socio-demographic factors. Prevalence in socio-demographic factor subgroups and overall were estimated. Rao-Scott adjusted chi-square tests were utilized to determine if between-group differences were present. Factor interactions were checked by logistic regression analyses. RESULTS: A total of 73,992 participants aged 6-16 years of age were selected in Stage 1. In Stage 2, 17,524 individuals were screened and diagnosed. The weighted prevalence of any disorder was 17.5% (95% CI: 17.2-18.0). Statistically significant differences in prevalence of any psychiatric disorder were observed between sexes [χ (1, N = 71,929) = 223.0, p < .001], age groups [χ (1, N = 71,929) = 18.6, p < .001] and developed vs. developing areas [χ (1, N = 71,929) = 2,129.6, p < .001], while no difference was found between rural and urban areas [χ (1, N = 71,929) = 1.4, p = .239]. Male, younger individuals, children, and adolescents from developed areas had higher prevalence of any psychiatric disorder. The prevalence of any psychiatric disorder was found to decrease with the age in the male group, while the female group increased with the age. Individuals diagnosed with attention-deficit hyperactivity disorder, oppositional defiant disorder, a tic disorder, conduct disorder, and major depression disorder had the highest rates of comorbidity. CONCLUSIONS: The prevalence of any psychiatric disorder we found is the highest ever reported in China. These results urgently need to be addressed by public mental health service providers and policymakers in order to provide access to the necessary treatments and to reduce the long-term negative impact of these conditions on families and the society as a whole.

25Association between adolescent depression and adult suicidal behavior: A systematic review and meta-analysis.PubMed

Cong Wang, Yingying Tong, Ting Tang, et al.
Asian J Psychiatr. 2024 Oct;100:104185. doi: 10.1016/j.ajp.2024.104185. Epub 2024 Jul 29.
This meta-analysis aims to estimate the association between adolescent depression and adult suicidal behavior, while systematically evaluating gender differences reported in literature. A random-effects model was used to determine the pooled association, reporting odds ratios (ORs) with corresponding 95 % confidence intervals (CIs). Nine articles comprising over 6084 adolescents together showed that people with a history of depression in adolescence are more likely to gain suicidal behaviors during adulthood (OR = 3.97, 95 % Cl: 2.79, 5.63). Sex-specific analysis indicated that males who experienced depression in adolescence developed a higher incidence of suicidal behavior in adulthood compared to females with a similar history (Males: OR = 3.61, 95 % Cl: 1.02, 12.78; Females: OR = 3.56, 95 % Cl: 1.71, 7.43). Furthermore, suicide attempts emerged as the predominant outcome among various suicidal behaviors (OR = 3.43, 95 % Cl: 1.75, 6.71). This meta-analysis provides robust evidence that depression in adolescence significantly increases the risk of suicidal behavior in adulthood.

26Prevalence and correlates of perinatal depression.PubMed

Khalood Al-Abri, Dawn Edge, Christopher J Armitage
Soc Psychiatry Psychiatr Epidemiol. 2023 Nov;58(11):1581-1590. doi: 10.1007/s00127-022-02386-9. Epub 2023 Jan 16.
PURPOSE: This systematic review of systematic reviews aims to provide the first global picture of the prevalence and correlates of perinatal depression, and to explore the commonalities and discrepancies of the literature. METHODS: Seven databases were searched from inception until April 2022. Full-text screening and data extraction were performed independently by two researchers and the AMSTAR tool was used to assess the methodological quality. RESULTS: 128 systematic reviews were included in the analysis. Mean overall prevalence of perinatal depression, antenatal depression and postnatal depression was 26.3%, 28.5% and 27.6%, respectively. Mean prevalence was significantly higher (27.4%; SD = 12.6) in studies using self-reported measures compared with structured interviews (17.0%, SD = 4.5; d = 1.0) and among potentially vulnerable populations (32.5%; SD = 16.7, e.g. HIV-infected African women) compared to the general population (24.5%; SD = 8.1; d = 0.6). Personal history of mental illness, experiencing stressful life events, lack of social support, lifetime history of abuse, marital conflicts, maternity blues, child care stress, chronic physical health conditions, preeclampsia, gestational diabetes mellitus, being exposed to second-hand smoke and sleep disturbance were among the major correlates of perinatal depression. CONCLUSION: Although the included systematic reviews were all of medium-high quality, improvements in the quality of primary research in this area should be encouraged. The standardisation of perinatal depression assessment, diagnosis and measurement, the implementation of longitudinal designs in studies, inclusions of samples that better represent the population and better control of potentially confounding variables are encouraged.

27Prevalence and Risk Factors of Postpartum Depression in Women: A Systematic Review and Meta-analysis.PubMed

Xueyan Liu, Shuhui Wang, Guangpeng Wang
J Clin Nurs. 2022 Oct;31(19-20):2665-2677. doi: 10.1111/jocn.16121. Epub 2021 Nov 8.
AIM: The current systematic review aimed to present the pooled estimated prevalence and risk factors of PPD. BACKGROUND: Postpartum depression seriously affects the physical and mental health of the mother and child. However, high-quality meta-analysis is limited, which restricts the screening and intervention of postpartum depression. DESIGN: A systematic review and meta-analysis. METHODS: Cochrane Library, PubMed, Embase and Web of Science were searched for cohort and case-control studies investigating the prevalence and risk factors of postpartum depression from inception to December 31st, 2020. Meta-analyses were performed to identify postpartum depression prevalence and risk factors using a random-effects model. RESULTS: Of the 33 citations evaluated, 27 reported the prevalence of postpartum depression in 33 separate study populations containing 133,313. SUBJECTS: Pooled prevalence in all studies was 14.0% (95%CI, 12.0%-15.0%). The prevalence varied according to country (from 5.0% to 26.32%) and developing countries, especially China, have a high prevalence of postpartum depression. The following risk factors were associated with postpartum depression: gestational diabetes mellitus(OR = 2.71, 95%CI 1.78-4.14, I = 0.0%), depression during pregnancy(OR = 2.40, 95%CI 1.96-2.93, I = 96.7%), pregnant women give birth to boys(OR = 1.62; 95%CI 1.28-2.05; I = 0.0%), history of depression during pregnancy(OR = 4.82, 95%CI 1.32-17.54, I = 74.9%), history of depression(OR = 3.09, 95%CI 1.62-5.93, I = 86.5%) and epidural anaesthesia during delivery(OR = .81, 95%CI .13-4.87, I = 90.1%). CONCLUSIONS: The prevalence of postpartum depression seems to be high, especially in developing countries. Gestational diabetes mellitus, depression during pregnancy, pregnant women give birth to boys, history of depression during pregnancy, history of depression, epidural anaesthesia during delivery were identified as risk factors for postpartum depression. Understanding the risk factors of PPD can provide the healthcare personnel with the theoretical basis for the patients' management and treatment. IMPLICATIONS FOR PRACTICE: This systematic review and meta-analysis identified six significant risk factors for PPD, which provides nurses with a theoretical basis for managing and treating women with PPD to effectively improve the screening rate, intervention rate and referral rate of women with PPD.

28Maternal mental health and infant emotional reactivity: a 20-year two-cohort study of preconception and perinatal exposures.PubMed

Elizabeth Spry, Margarita Moreno-Betancur, Denise Becker, et al.
Psychol Med. 2020 Apr;50(5):827-837. doi: 10.1017/S0033291719000709. Epub 2019 Apr 10.
BACKGROUND: Maternal mental health during pregnancy and postpartum predicts later emotional and behavioural problems in children. Even though most perinatal mental health problems begin before pregnancy, the consequences of preconception maternal mental health for children's early emotional development have not been prospectively studied. METHODS: We used data from two prospective Australian intergenerational cohorts, with 756 women assessed repeatedly for mental health problems before pregnancy between age 13 and 29 years, and during pregnancy and at 1 year postpartum for 1231 subsequent pregnancies. Offspring infant emotional reactivity, an early indicator of differential sensitivity denoting increased risk of emotional problems under adversity, was assessed at 1 year postpartum. RESULTS: Thirty-seven percent of infants born to mothers with persistent preconception mental health problems were categorised as high in emotional reactivity, compared to 23% born to mothers without preconception history (adjusted OR 2.1, 95% CI 1.4-3.1). Ante- and postnatal maternal depressive symptoms were similarly associated with infant emotional reactivity, but these perinatal associations reduced somewhat after adjustment for prior exposure. Causal mediation analysis further showed that 88% of the preconception risk was a direct effect, not mediated by perinatal exposure. CONCLUSIONS: Maternal preconception mental health problems predict infant emotional reactivity, independently of maternal perinatal mental health; while associations between perinatal depressive symptoms and infant reactivity are partially explained by prior exposure. Findings suggest that processes shaping early vulnerability for later mental disorders arise well before conception. There is an emerging case for expanding developmental theories and trialling preventive interventions in the years before pregnancy.

29Gestational diabetes mellitus and peripartum depression: a longitudinal study of a bidirectional relationship.PubMed

Maja Žutić, Marijana Matijaš, Jasminka Štefulj, et al.
BMC Pregnancy Childbirth. 2024 Dec 19;24(1):821. doi: 10.1186/s12884-024-07046-1.
BACKGROUND: Gestational diabetes mellitus (GDM) and peripartum depression (PPD) are increasing global health issues with potentially long-lasting adverse outcomes. While limited studies suggest a bidirectional relationship between GDM and PPD, most research has been cross-sectional and focused on one direction of the relationship, primarily if GDM predicts postpartum depression. The interplay between antenatal depression and GDM is less explored, with a critical lack of prospective bidirectional studies. This longitudinal study aimed to investigate the bidirectional relationship between GDM and PPD in a total sample and according to different pre-pregnancy body mass index (BMI) categories. Specifically, we examined whether antenatal depression symptoms predict a subsequent GDM diagnosis and whether GDM predicts subsequent postpartum depression symptoms. METHODS: A three-wave online longitudinal study included 360 women who were followed from the second trimester (20-28 weeks, T1) through the third trimester (32-42 weeks, T2), and into the postpartum period (6-20 weeks after birth, T3). Participants completed the General Data Questionnaire, one item about the diagnosis of GDM, and the Edinburgh Postnatal Depression Scale (EPDS). The sample was stratified according to pre-pregnancy BMI into normal-weight (N = 247) and overweight/obese (N = 113) subgroups. Women with type I and II diabetes, GDM at T1, and underweight BMI were excluded. RESULTS: In the total sample, antenatal depression symptoms predicted GDM, whereas GDM did not predict postpartum depression symptoms. A bidirectional relationship was observed in normal-weight women, where antenatal depression symptoms predicted subsequent GDM diagnosis, and GDM diagnosis predicted postpartum depression symptoms. In contrast, no associations were found in either direction in the overweight/obese subgroup. CONCLUSIONS: This study provides evidence of a bidirectional relationship between GDM and PPD only in women with normal body weight before pregnancy. The results highlight the complexity of the relationship between peripartum mental and metabolic health, that is dependent on pre-pregnancy BMI. Clinicians should be aware that normal-weight women may have a unique sensitivity to the bidirectional interplay between GDM and PPD. Pregnant women should be closely monitored for both mental and metabolic health issues and targeted for prevention programs to reduce the risks and burdens associated with both conditions.

30Frailty and depressive symptoms in relation to cardiovascular disease risk in middle-aged and older adults.PubMed

Zheng Zhang, Huijie Xu, Runjia Zhang, et al.
Nat Commun. 2025 Jul 1;16(1):6008. doi: 10.1038/s41467-025-61089-2.
As global aging accelerates, frailty and depressive symptoms have emerged as critical contributors to cardiovascular disease (CVD) risk among older adults. However, the dynamic interplay between these factors remains underexplored. Here, we examine the associations among frailty, depressive symptoms, and incident CVD using data from five international cohorts (HRS, CHARLS, SHARE, ELSA, MHAS) involving individuals aged 50 and above. Our findings reveal that frailty significantly increases CVD risk, with depressive symptoms partially mediating this relationship. Transitions into frailty elevate CVD risk, while improvements reduce it. Cross-lagged panel network analysis identifies consistent CVD predictors, including hypertension, diabetes, and mobility issues. Subgroups with stronger associations include frail males, older individuals, working or retired people, and those with unhealthy lifestyles. These results underscore the need for integrated interventions targeting frailty and depressive symptoms to prevent CVD in aging populations.

31Investigating intrinsic and situational predictors of depression among older adults: An analysis of the CHARLS database.PubMed

Yafei Wu, Chongtao Wei, Yaheng Zhang, et al.
Asian J Psychiatr. 2024 Dec;102:104279. doi: 10.1016/j.ajp.2024.104279. Epub 2024 Oct 17.
BACKGROUND: This study aimed to investigate the intrinsic and situational predictors of depression under the health ecological model. METHODS: Two waves (2011 and 2013) of survey data were collected from the CHARLS. A total of 5845 older adults (≧60) were included, and depression was defined as CESD-10 score ≧10. Random forest combined with interpretable methods were utilized to select important predictors of depression. Multilevel logit model was used to examine the associations of intrinsic and situational predictors with depression. RESULTS: After a 2-year follow up, 1822 individuals (31.17 %) developed depression. Interpretable analyses showed that both intrinsic and situational variables were predictive for depression. Multilevel logit model showed that age, gender, number of chronic diseases, number of pain areas, life satisfaction, and toilet distance were significantly associated with depression. CONCLUSION: Both intrinsic and situational factors were found to be associated with depression among community older population, highlighting their significance for early prevention from the perspective of public health.

32Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential.PubMed

Minlan Yuan, Biao Yang, Gerson Rothschild, et al.
Signal Transduct Target Ther. 2023 Aug 30;8(1):309. doi: 10.1038/s41392-023-01519-z.
Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30-40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.

33Epigenetics of depression.PubMed

Sermsak Lolak, Pim Suwannarat, Robert H Lipsky
Prog Mol Biol Transl Sci. 2014;128:103-37. doi: 10.1016/B978-0-12-800977-2.00005-X.
Major depressive disorder (MDD) is a leading cause of disability worldwide and is associated with poor psychological, medical, and socioeconomic outcomes. Although much has been learned about the etiology and treatment options of MDD over the past decade, there remain unanswered questions that pose challenges to improving acute and chronic outcomes for those with MDD. MDD is a clinically heterogeneous disorder. Genetic studies to date have indicated a number of genes, including transporters, neurotransmitters, neurotrophins, and their associated signaling networks that may predispose individuals to MDD and may also predict treatment outcomes. However, twin studies indicate that genes account for only a small degree of the variation in MDD. Thus, other mechanisms, through epigenetic marks, may act to form a molecular memory of previous gene-to-environment interactions and to establish vulnerabilities (or, conversely, resistance) to MDD. Current evidence supports a role for pre-, peri-, and early postnatal adversities and stressful life events into adulthood affecting epigenetic patterns, providing a mechanistic foundation to develop epigenetic marks as biomarkers for MDD. This review presents the evidence supporting a role for epigenetic effects in MDD and in treatment response. We also discuss the controversy behind modulating epigenetic mechanisms in long-term antidepressant pharmacotherapy.

34Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies.PubMed

Cell. 2025 Feb 6;188(3):640-652.e9. doi: 10.1016/j.cell.2024.12.002. Epub 2025 Jan 14.
In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.

35Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.PubMed

David M Howard, Mark J Adams, Toni-Kim Clarke, et al.
Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

36Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.PubMed

Thomas D Als, Mitja I Kurki, Jakob Grove, et al.
Nat Med. 2023 Jul;29(7):1832-1844. doi: 10.1038/s41591-023-02352-1. Epub 2023 Jul 18.
Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

37Polygenic prediction via Bayesian regression and continuous shrinkage priors.PubMed

Tian Ge, Chia-Yen Chen, Yang Ni, et al.
Nat Commun. 2019 Apr 16;10(1):1776. doi: 10.1038/s41467-019-09718-5.
Polygenic risk scores (PRS) have shown promise in predicting human complex traits and diseases. Here, we present PRS-CS, a polygenic prediction method that infers posterior effect sizes of single nucleotide polymorphisms (SNPs) using genome-wide association summary statistics and an external linkage disequilibrium (LD) reference panel. PRS-CS utilizes a high-dimensional Bayesian regression framework, and is distinct from previous work by placing a continuous shrinkage (CS) prior on SNP effect sizes, which is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local LD patterns. Simulation studies using data from the UK Biobank show that PRS-CS outperforms existing methods across a wide range of genetic architectures, especially when the training sample size is large. We apply PRS-CS to predict six common complex diseases and six quantitative traits in the Partners HealthCare Biobank, and further demonstrate the improvement of PRS-CS in prediction accuracy over alternative methods.

38Identification of common genetic risk variants for autism spectrum disorder.PubMed

Jakob Grove, Stephan Ripke, Thomas D Als, et al.
Nat Genet. 2019 Mar;51(3):431-444. doi: 10.1038/s41588-019-0344-8. Epub 2019 Feb 25.
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

39Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.PubMed

Andreas J Forstner, Swapnil Awasthi, Christiane Wolf, et al.
Mol Psychiatry. 2021 Aug;26(8):4179-4190. doi: 10.1038/s41380-019-0590-2. Epub 2019 Nov 11.
Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

40Epigenetics and depression
.PubMed

Signe Penner-Goeke, Elisabeth B Binder
Dialogues Clin Neurosci. 2019 Dec;21(4):397-405. doi: 10.31887/DCNS.2019.21.4/ebinder.
The risk for major depression is both genetically and environmentally determined. It has been proposed that epigenetic mechanisms could mediate the lasting increases in depression risk following exposure to adverse life events and provide a mechanistic framework within which genetic and environmental factors can be integrated. Epigenetics refers to processes affecting gene expression and translation that do not involve changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as well as histone modifications. Here we review evidence for a role of epigenetics in the pathogenesis of depression from studies investigating DNAm, miRNAs, and histone modifications using different tissues and various experimental designs. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant epigenetic mechanisms targeting stress response pathways, neuronal plasticity, and other behaviorally relevant pathways that have been implicated in major depression. .

41Epigenetic signaling in schizophrenia.PubMed

Daisuke Ibi, Javier González-Maeso
Cell Signal. 2015 Oct;27(10):2131-6. doi: 10.1016/j.cellsig.2015.06.003. Epub 2015 Jun 26.
Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Psychiatric disorders such as schizophrenia and depression are complex and heterogeneous diseases with multiple and independent factors that may contribute to their pathophysiology, making challenging to find a link between specific elements and the underlying mechanisms responsible for the disorder and its treatment. Growing evidences suggest that epigenetic modifications in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychiatric conditions throughout life. This review focuses on recent advances that directly implicate epigenetic modifications in schizophrenia and antipsychotic drug action.

42Stress, epigenetics and depression: A systematic review.PubMed

Caroline Park, Joshua D Rosenblat, Elisa Brietzke, et al.
Neurosci Biobehav Rev. 2019 Jul;102:139-152. doi: 10.1016/j.neubiorev.2019.04.010. Epub 2019 Apr 18.
Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR, LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation.

43Could epigenetics help explain racial disparities in chronic pain?PubMed

Edwin N Aroke, Paule V Joseph, Abhrarup Roy, et al.
J Pain Res. 2019 Feb 18;12:701-710. doi: 10.2147/JPR.S191848. eCollection 2019.
African Americans disproportionately suffer more severe and debilitating morbidity from chronic pain than do non-Hispanic Whites. These differences may arise from differential exposure to psychosocial and environmental factors such as adverse childhood experiences, racial discrimination, low socioeconomic status, and depression, all of which have been associated with chronic stress and chronic pain. Race, as a social construct, makes it such that African Americans are more likely to experience different early life conditions, which may induce epigenetic changes that sustain racial differences in chronic pain. Epigenetics is one mechanism by which environmental factors such as childhood stress, racial discrimination, economic hardship, and depression can affect gene expression without altering the underlying genetic sequence. This article provides a narrative review of the literature on epigenetics as a mechanism by which differential environmental exposure could explain racial differences in chronic pain. Most studies of epigenetic changes in chronic pain examine DNA methylation. DNA methylation is altered in the glucocorticoid (stress response) receptor gene, , which has been associated with depression, childhood stress, low socioeconomic status, and chronic pain. Similarly, DNA methylation patterns of immune cytokine genes have been associated with chronic stress states. Thus, DNA methylation changes may play an essential role in the epigenetic modulation of chronic pain in different races with a higher incidence of epigenetic alterations contributing to more severe and disabling chronic pain in African Americans.

44Integrated analysis of multi-omics data on epigenetic changes caused by combined exposure to environmental hazards.PubMed

So Yeon Yu, Eun Jung Koh, Seung Hwan Kim, et al.
Environ Toxicol. 2021 Jun;36(6):1001-1010. doi: 10.1002/tox.23099. Epub 2021 Jan 13.
Humans are easily exposed to environmentally hazardous factors in industrial sites or daily life. In addition, exposure to various substances and not just one harmful substance is common. However, research on the effects of combined exposure on humans is limited. Therefore, this study examined the effects of combined exposure to volatile organic compounds (VOCs) on the human body. We separated 193 participants into four groups according to their work-related exposure (nonexposure, toluene exposure, toluene and xylene exposure, and toluene, ethylbenzene, and xylene exposure). We then identified the methylation level and long noncoding RNA (lncRNA) levels by omics analyses, and performed an integrated analysis to examine the change of gene expression. Thereafter, the effects of combined exposure to environmental hazards on the human body were investigated and analyzed. Exposure to VOCs was found to negatively affect the development and maintenance of the nervous system. In particular, the MALAT1 lncRNA was found to be significantly reduced in the complex exposure group, and eight genes were significantly downregulated by DNA hypermethylation. The downregulation of these genes could cause a possible decrease in the density of synapses as well as the number and density of dendrites and spines. In summary, we found that increased combined exposure to environmental hazards could lead to additional epigenetic changes, and consequently abnormal dendrites, spines, and synapses, which could damage motor learning or spatial memory. Thus, lncRNA MALAT1 or FMR1 could be novel biomarkers of neurotoxicity to identify the negative health effects of VOC complex exposure.

45Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior.PubMed

Amni Al-Kachak, Giuseppina Di Salvo, Sasha L Fulton, et al.
Nat Commun. 2024 Jun 13;15(1):5042. doi: 10.1038/s41467-024-49336-4.
Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.

46Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress.PubMed

Angélica Torres-Berrío, Molly Estill, Vishwendra Patel, et al.
Neuron. 2024 Sep 4;112(17):2973-2989.e10. doi: 10.1016/j.neuron.2024.06.006. Epub 2024 Jul 2.
Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.

47Glucose metabolism impairment in major depressive disorder.PubMed

Fanhao Meng, Jing Wang, Long Wang, et al.
Brain Res Bull. 2025 Feb;221:111191. doi: 10.1016/j.brainresbull.2025.111191. Epub 2025 Jan 7.
Major depressive disorder (MDD) is a common mental disorder with chronic tendencies that seriously affect regular work, life, and study. However, its exact pathogenesis remains unclear. Patients with MDD experience systemic and localized impairments in glucose metabolism throughout the disease course, disrupting various processes such as glucose uptake, glycoprotein transport, glycolysis, the tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). These impairments may result from mechanisms including insulin resistance, hyperglycemia-induced damage, oxidative stress, astrocyte abnormalities, and mitochondrial dysfunction, leading to insufficient energy supply, altered synaptic plasticity, neuronal cell death, and functional and structural damage to reward networks. These mechanical changes contribute to the pathogenesis of MDD and severely interfere with the prognosis. Herein, we summarized the impairment of glucose metabolism and its pathophysiological mechanisms in patients with MDD. In addition, we briefly discussed potential pharmacological interventions for glucose metabolism to alleviate MDD, including glucagon-like peptide-1 receptor agonists, metformin, topical insulin, liraglutide, and pioglitazone, to encourage the development of new therapeutics.

48Targeting PDK2 rescues stress-induced impaired brain energy metabolism.PubMed

Changshui Wang, Changmeng Cui, Pengfei Xu, et al.
Mol Psychiatry. 2023 Oct;28(10):4138-4150. doi: 10.1038/s41380-023-02098-9. Epub 2023 May 15.
Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.

49Regulation of leukocyte tricarboxylic acid cycle in drug-naïve Bipolar Disorder.PubMed

Rafael T de Sousa, Emilio L Streck, Orestes V Forlenza, et al.
Neurosci Lett. 2015 Sep 25;605:65-8. doi: 10.1016/j.neulet.2015.08.022. Epub 2015 Aug 20.
Several lines of evidence suggest a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder (BD). The tricarboxylic acid cycle (TCA cycle) is fundamental for mitochondrial energy production and produces substrates used in oxidative phosphorylation by the mitochondrial electron transport chain. The activity of the key TCA cycle enzymes citrate synthase, malate dehydrogenase, and succinate dehydrogenase has never been evaluated in BD. In the present study, these enzymes were assayed from leukocytes of drug-naïve BD patients in a major depressive episode (n=18) and compared to 24 age-matched healthy controls. Drug-naïve BD patients did not show differences in activities of citrate synthase (p=0.79), malate dehydrogenase (p=0.17), and succinate dehydrogenase (p=0.35) compared with healthy controls. No correlation between any TCA cycle enzyme activity and severity of depressive symptoms was observed. Overall, these data suggest that the activities of the TCA cycle enzymes are not altered in major depressive episodes of recent-onset BD, which may support the concept of illness staging and neuroprogression in BD.

50Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility.PubMed

Jonathan M Borkum
Neurochem Res. 2021 Aug;46(8):1913-1932. doi: 10.1007/s11064-021-03335-9. Epub 2021 Apr 30.
People with migraine are prone to a brain energy deficit between attacks, through increased energy demand (hyperexcitable brain) or decreased supply (mitochondrial impairment). However, it is uncertain how this precipitates an acute attack. Here, the central role of oxidative stress is adduced. Specifically, neurons' antioxidant defenses rest ultimately on internally generated NADPH (reduced nicotinamide adenine dinucleotide phosphate), whose levels are tightly coupled to energy production. Mitochondrial NADPH is produced primarily by enzymes involved in energy generation, including isocitrate dehydrogenase of the Krebs (tricarboxylic acid) cycle; and an enzyme, nicotinamide nucleotide transhydrogenase (NNT), that depends on the Krebs cycle and oxidative phosphorylation to function, and that works in reverse, consuming antioxidants, when energy generation fails. In migraine aura, cortical spreading depression (CSD) causes an initial severe drop in level of NADH (reduced nicotinamide adenine dinucleotide), causing NNT to impair antioxidant defense. This is followed by functional hypoxia and a rebound in NADH, in which the electron transport chain overproduces oxidants. In migraine without aura, a similar biphasic fluctuation in NADH very likely generates oxidants in cortical regions farthest from capillaries and penetrating arterioles. Thus, the perturbations in brain energy demand and/or production seen in migraine are likely sufficient to cause oxidative stress, triggering an attack through oxidant-sensing nociceptive ion channels. Implications are discussed for the development of new classes of migraine preventives, for the current use of C57BL/6J mice (which lack NNT) in preclinical studies of migraine, for how a microembolism initiates CSD, and for how CSD can trigger a migraine.

51The association between Diabetes mellitus and Depression.PubMed

S V Bădescu, C Tătaru, L Kobylinska, et al.
J Med Life. 2016 Apr-Jun;9(2):120-5.
UNLABELLED: Depression occurrence is two to three times higher in people with diabetes mellitus, the majority of the cases remaining under-diagnosed. The purpose of this review was to show the links between depression and diabetes, point out the importance of identifying depression in diabetic patients and identify the possible ways to address both diseases. Possible common pathophysiological mechanisms as stress and inflammation were explained, while emphasis was made on screening for depression in diabetic patients. An important aspect for the diabetic specialist would be the understanding of the common origins of diabetes and depression and the awareness of this quite common comorbidity, in order to improve the outcomes of both diseases. ABBREVIATIONS: DALYS = disability adjusted life years, DSM-5 = American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, DM1 = Type 1 diabetes mellitus, DM2 = Type 2 diabetes mellitus, HPA-axis = hypothalamus - pituitary - adrenal axis, SNS = sympathetic nervous system, BDI = Beck Depression Inventory, CES-D = Centre for Epidemiologic Studies Depression Scale, HADS = Hospital Anxiety and Depression Scale, PHQ = Patient Health Questionnaire.

52Depression and diabetes.PubMed

Norman Sartorius
Dialogues Clin Neurosci. 2018 Mar;20(1):47-52. doi: 10.31887/DCNS.2018.20.1/nsartorius.
The comorbidity of mental and physical disorders is a major challenge for health care worldwide. Its prevalence is increasing and is likely to continue to grow due to the increase in life expectancy and a variety of other reasons. The comorbidity of depression and diabetes can be seen as a prototypical example of mental/physical comorbidity. The prevalence of both conditions is growing, and depression is twice as frequent in people with diabetes compared with those without diabetes. Health services are by and large inadequately prepared to deal with comorbid depression and diabetes, and the increasing specialization (and fragmentation) of medicine will probably make things worse. This paper reviews the epidemiology and risk factors of the comorbidity of depression and diabetes and describes areas that should be given attention in order to reduce problems arising as a result of the comorbidity of these two conditions.

53Depression in type 2 diabetes mellitus: prevalence, impact, and treatment.PubMed

Katherine Semenkovich, Miriam E Brown, Dragan M Svrakic, et al.
Drugs. 2015 Apr;75(6):577-87. doi: 10.1007/s40265-015-0347-4.
Clinically significant depression is present in one of every four people with type 2 diabetes mellitus (T2DM). Depression increases the risk of the development of T2DM and the subsequent risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications. Conversely, a diagnosis of T2DM increases the risk of incident depression and can contribute to a more severe course of depression. This linkage reflects a shared etiology consisting of complex bidirectional interactions among multiple variables, a process that may include autonomic and neurohormonal dysregulation, weight gain, inflammation, and hippocampal structural alterations. Two recent meta-analyses of randomized controlled depression treatment trials in patients with T2DM concluded that psychotherapy and antidepressant medication (ADM) were each moderately effective for depression and that cognitive behavior therapy (CBT) had beneficial effects on glycemic control. However, the number of studies (and patients exposed to randomized treatment) included in these analyses is extremely small and limits the certainty of conclusions that can be drawn from the data. Ultimately, there is no escaping the paucity of the evidence base and the need for additional controlled trials that specifically address depression management in T2DM. Future trials should determine both the effects of treatment and the change in depression during treatment on measures of mood, glycemic control, and medical outcome.

54Diabetes and depression.PubMed

Antonio Campayo, Carlos H Gómez-Biel, Antonio Lobo
Curr Psychiatry Rep. 2011 Feb;13(1):26-30. doi: 10.1007/s11920-010-0165-z.
In a context of the potentially epidemic nature of both diabetes mellitus and depression, and the negative effects reported in cases of comorbidity, this review suggests that the association of the two conditions is multifaceted. Increased risks of prevalent depression and incident depression among diabetic patients have been reported in community studies. Even more consistent is the finding supporting psychosomatic hypotheses regarding the increased risk of diabetes among depressed patients. A recent relevant finding is the increased risk of diabetes reported in depression that is commonly found in the community, namely nonsevere, persistent, untreated depression. In view of the negative implications of the comorbidity of depression and diabetes, the suggestion that all clinically relevant cases of depression found in the community should be treated seems logical. However, new studies seem mandatory to document the efficacy of treatment of depression and the safety of antidepressant use in cases of comorbidity.

55Regulation of lipid metabolism by sphingolipids.PubMed

Tilla S Worgall
Subcell Biochem. 2008;49:371-85. doi: 10.1007/978-1-4020-8830-8_14.
Sphingolipids, together with phospholipids and cholesterol are key components of membrane lipid bilayers, contribute to specialized membrane domains called rafts and function as signaling molecules. Sphingolipids have been recognized to exert a distinct role in the post-transcriptional regulation of the sterol-regulatory element binding proteins (SREBPs), key transcription factors of lipid synthesis. Sphingolipid synthesis is an obligate activator of SREBP. Inhibition of sphingolipid synthesis decreases SREBP on a post-transcriptional level. With the exception of enzymes that synthesize sphingolipids, SREBPs regulate the transcription of key enzymes that synthesize cholesterol, phospholipids and fatty acids. This observation suggests an exclusive role for sphingolipids in the regulation of lipid metabolism. Although exact mechanisms how sphingolipids regulate lipid metabolism are currently not known, this relationship has important implications with regard to cellular lipid homeostasis, composition of lipoproteins and development of atherosclerosis.

56Saikosaponin antidepressant mechanism: Improving the sphingolipid metabolism in the cortex via Apolipoprotein E and triggering neurovascular coupling.PubMed

Yonggui Song, Meixizi Lai, Zhou Liao, et al.
Phytomedicine. 2024 Sep;132:155829. doi: 10.1016/j.phymed.2024.155829. Epub 2024 Jun 20.
BACKGROUND: Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works. PURPOSE: In this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms. METHODS: APOE mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant. RESULTS: APOE mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice. CONCLUSION: Our study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.

57The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases.PubMed

Masayuki Nagahashi, Kizuki Yuza, Yuki Hirose, et al.
J Lipid Res. 2016 Sep;57(9):1636-43. doi: 10.1194/jlr.R069286. Epub 2016 Jul 26.
Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases.

58Multi-omics data reveals the disturbance of glycerophospholipid metabolism caused by disordered gut microbiota in depressed mice.PubMed

Tian Tian, Qiang Mao, Jing Xie, et al.
J Adv Res. 2022 Jul;39:135-145. doi: 10.1016/j.jare.2021.10.002. Epub 2021 Oct 13.
INTRODUCTION: Although researchers have done intensive research on depression, its pathogenesis is still not fully explained. More and more evidence suggests that gut microbiota is closely related to the onset of depression; but its specific functional ways are not clearly identified. OBJECTIVES: The purpose of our work was to find out how the gut microbiota was involved in the onset of depression, and to identify the potential ways to link the gut and brain in mice with depressive-like behaviors (DLB). METHODS: We used the chronic restraint stress (CRS)-induced depression model here. Gut microbiota compositions in fecal samples, lipid metabolism (in fecal, serum and hippocampus samples) and neurotransmitters in hippocampus samples were detected. RESULTS: We found that the 7 of 13 differential genera that significantly correlated with DLB belonged to phylum Firmicutes. The differential lipid metabolites in fecal samples mainly belonged to glycerophospholipids (GP) and fatty acids (FA) metabolism, and three important "metabolite type-bacterial taxa" correlated pairs were identified: "FA/GP-Firmicutes", "FA/GP-Akkermansia", and "FA/GP-Bifidobacterium". The key differential lipid metabolites significantly correlated with DLB mainly belonged to FA and GP, and the DLB-related metagenomic genes were consistently enriched in GP metabolism and FA metabolism. Three significantly changed short-chain fatty acids (SCFAs) were significantly correlated with the majority of differential genera. Meanwhile, we found that the differential lipid metabolites in serum and hippocampus samples were mainly mapped into the GP metabolism, and there were four differential neurotransmitters from the tryptophan pathway in hippocampus samples. CONCLUSION: Together, our findings could provide novel insights into the role of "microbiota-gut-brain" (MGB) axis in depression, and indicate that the gut microbiota might have a vital role in the onset of DLB by affecting the peripheral/central GP metabolism and tryptophan pathway. The "Firmicutes-SCFAs-GP metabolism-Tryptophan pathway" might be a possible way to link the gut and brain in depressed mice.

59Gut microbiota and its metabolites in depression: from pathogenesis to treatment.PubMed

Lanxiang Liu, Haiyang Wang, Xueyi Chen, et al.
EBioMedicine. 2023 Apr;90:104527. doi: 10.1016/j.ebiom.2023.104527. Epub 2023 Mar 22.
Major depressive disorder is one of the most disabling mental disorders worldwide. Increasing preclinical and clinical studies have highlighted that compositional and functional (e.g., metabolite) changes in gut microbiota, known as dysbiosis, are associated with the onset and progression of depression via regulating the gut-brain axis. However, the gut microbiota and their metabolites present a double-edged sword in depression. Dysbiosis is involved in the pathogenesis of depression while, at the same time, offering a novel therapeutic target. In this review, we describe the association between dysbiosis and depression, drug-microbiota interactions in antidepressant treatment, and the potential health benefits of microbial-targeted therapeutics in depression, including dietary interventions, fecal microbiota transplantation, probiotics, prebiotics, synbiotics, and postbiotics. With the emergence of microbial research, we describe a new direction for future research and clinical treatment of depression.

60Brain-gut-microbiota axis in depression: A historical overview and future directions.PubMed

Lijia Chang, Yan Wei, Kenji Hashimoto
Brain Res Bull. 2022 May;182:44-56. doi: 10.1016/j.brainresbull.2022.02.004. Epub 2022 Feb 11.
Depression is the most common mental disorder and a leading cause of disability worldwide. Despite abundant research, the precise mechanisms underlying the pathophysiology of depression remain elusive. Accumulating evidence from preclinical and clinical studies suggests that alterations in the gut microbiota, microbe-derived short-chain fatty acids, D-amino acids and metabolites play a key role in the pathophysiology of depression via the brain-gut-microbiota axis, including the neural and immune systems. Notably, the brain-gut-microbiota axis might play a crucial role in susceptibility versus resilience in rodents exposed to stress. Vagotomy is reported to block depression-like phenotypes in rodents after fecal microbiota transplantation of "depression-related" microbiome, suggesting that the vagus nerve influences depression through the brain-gut-microbiota axis. In this article, we review recent findings regarding the brain-gut-microbiota axis in depression and discuss its potential as a therapeutic target for depression.

61Neuroinflammation, Microbiota-Gut-Brain Axis, and Depression: The Vicious Circle.PubMed

Sandy Reyes-Martínez, Lorena Segura-Real, Ana Pamela Gómez-García, et al.
J Integr Neurosci. 2023 May 8;22(3):65. doi: 10.31083/j.jin2203065.
Depression is the leading cause of disability worldwide, contributing to the global disease burden. From above, it is a priority to investigate models that fully explain its physiopathology to develop new treatments. In the last decade, many studies have shown that gut microbiota (GM) dysbiosis influences brain functions and participate, in association with immunity, in the pathogenesis of depression. Thereby, GM modulation could be a novel therapeutic target for depression. This review aims to evidence how the GM and the immune system influence mental illness, particularly depression. Here, we focus on the communication mechanisms between the intestine and the brain and the impact on the development of neuroinflammation contributing to the development of Major Depressive Disorder (MDD). However, most of the current findings are in animal models, suggesting the need for studies in humans. In addition, more analysis of metabolites and cytokines are needed to identify new pathophysiological mechanisms improving anti-depression treatments.

62The gut microbiota in anxiety and depression - A systematic review.PubMed

Carra A Simpson, Carmela Diaz-Arteche, Djamila Eliby, et al.
Clin Psychol Rev. 2021 Feb;83:101943. doi: 10.1016/j.cpr.2020.101943. Epub 2020 Oct 29.
Growing evidence indicates the community of microorganisms throughout the gastrointestinal tract, (i.e., gut microbiota), is associated with anxiety and depressive disorders. We present the first systematic review of the gut microbiota in anxiety disorders, along with an update in depression. Consideration of shared underlying features is essential due to the high rates of comorbidity. Systematic searches, following PRISMA guidelines, identified 26 studies (two case-control comparisons of the gut microbiota in generalised anxiety disorder, 18 in depression, one incorporating both anxiety/depression, and five including symptom-only measures). Alpha and beta diversity findings were inconsistent; however, differences in bacterial taxa indicated disorders may be characterised by a higher abundance of proinflammatory species (e.g., Enterobacteriaceae and Desulfovibrio), and lower short-chain fatty acid producing-bacteria (e.g., Faecalibacterium). Several taxa, and their mechanisms of action, may relate to anxiety and depression pathophysiology via communication of peripheral inflammation to the brain. Although the gut microbiota remains a promising target for prevention and therapy, future research should assess confounders, particularly diet and psychotropic medications, and should examine microorganism function.

63Prebiotic inulin alleviates anxiety and depression-like behavior in alcohol withdrawal mice by modulating the gut microbiota and 5-HT metabolism.PubMed

Kuan Li, Wei Wei, Chongchong Xu, et al.
Phytomedicine. 2024 Dec;135:156181. doi: 10.1016/j.phymed.2024.156181. Epub 2024 Oct 28.
BACKGROUND: Alcohol dependence (AD) is a common psychiatric disorder, often accompanied by anxiety and depression. These comorbidities are linked to disturbances in serotonin (5-HT) metabolism and gut microbiota dysbiosis. Clinical studies suggest that inulin, a prebiotic, can alleviate anxiety and depression in AD patients by affecting the gut microbiota, although the mechanisms remain unclear. PURPOSE: The purpose of this study is to investigate the potential mechanisms by which inulin, a prebiotic, improves anxiety and depression-like behaviors in AD withdrawal mice. This research is based on the drug and food homology and intestinal treatment of encephalopathy, with the goal of developing new clinical strategies for AD treatment. STUDY DESIGN: For this purpose, fecal samples from AD patients were analyzed to identify microorganisms associated with AD. An AD withdrawal mouse model was created, with inulin as the intervention and fluvoxamine maleate as the control. Techniques such as 16S microbiome sequencing and UPLC-TQMS-targeted metabolomics were used to assess gut microbiota, short-chain fatty acids (SCFAs) levels, and 5-HT metabolism. METHODS: The AD withdrawal model was built using the "Drinking-in-the-dark" protocol over 6 weeks. Inulin (2 g/kg/day) and fluvoxamine maleate (30 mg/kg/day) were administered for 4 weeks. The open field test, forced swim test, and tail suspension test were used to evaluate anxiety and depression-like behaviors in mice. ELISA and qRT-PCR assessed 5-HT metabolism in the colon, blood, and prefrontal cortex, while 16S microbiome sequencing analyzed changes in gut microbiota and UPLC-TQMS examined SCFAs levels. Immunohistochemistry was used to study intestinal barrier integrity. RESULTS: AD patients showed reduced SCFA-producing bacteria such as Faecalibacterium and Roseburia. In mice, AD withdrawal led to anxiety and depression-like behaviors, disrupted 5-HT metabolism, and gut microbiota dysbiosis. Inulin supplementation alleviated these behaviors, increased 5-HT and 5-hydroxytryptophan (5-HTP) levels, upregulated colonic tryptophan hydroxylase 1 (TPH1) expression, and promoted the growth of beneficial bacteria such as Faecalibacterium and Roseburia, while also increasing SCFAs levels. CONCLUSION: Inulin increases the abundance of Faecalibacterium and Roseburia, enhances SCFAs production, and regulates 5-HT metabolism, improving anxiety and depression-like behaviors in AD withdrawal mice. These findings suggest that inulin may serve as a nutritional intervention for mental health in AD patients by targeting the microbiome-gut-brain axis.

64Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis.PubMed

Nuo Chen, Xinyi Xu, Yaxin Guo, et al.
Research (Wash D C). 2024 Jun 27;7:0400. doi: 10.34133/research.0400. eCollection 2024.
Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.

65Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities.PubMed

Gislaine Z Réus, Luana M Manosso, João Quevedo, et al.
Neurosci Biobehav Rev. 2023 Dec;155:105425. doi: 10.1016/j.neubiorev.2023.105425. Epub 2023 Oct 16.
Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation.

66Advancing an Inflammatory Subtype of Major Depression.PubMed

Andrew H Miller
Am J Psychiatry. 2025 Jun 1;182(6):516-524. doi: 10.1176/appi.ajp.20250289. Epub 2025 May 7.
Chronic inflammation plays a prominent role in multiple medical disorders, including psychiatric diseases such as major depression. Exposure to inflammatory stimuli leads to changes in neurotransmitter systems and neurocircuits in the brain that are associated with depressive symptoms. Blockade of inflammatory cytokines can reduce depressive symptoms in medically ill and medically healthy individuals with depression. Increased levels of biomarkers of inflammation are associated with an overrepresentation of neurovegetative symptoms, including anhedonia, fatigue, and psychomotor slowing, and can predict response to antidepressant treatments. Importantly, however, increased inflammatory biomarkers occur in only a subgroup of individuals with depression. Thus, there appears to be a subset of patients with depression with a unique symptom presentation and treatment response whose disease is primarily driven by inflammation. Further identifying and characterizing this inflammatory subtype of depression can foster the development of treatments targeting the immune system and its effects on the brain. Moreover, by using this mechanism-based approach to parsing the heterogeneity of depression, we can refine our diagnostic nosology and model a strategy for precision medicine and targeted therapeutics in psychiatry.

67Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.PubMed

Andrew H Miller, Vladimir Maletic, Charles L Raison
Biol Psychiatry. 2009 May 1;65(9):732-41. doi: 10.1016/j.biopsych.2008.11.029. Epub 2009 Jan 15.
Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

68C-Reactive Protein as a Biomarker for Major Depressive Disorder?PubMed

Laura Orsolini, Simone Pompili, Silvia Tempia Valenta, et al.
Int J Mol Sci. 2022 Jan 30;23(3):1616. doi: 10.3390/ijms23031616.
The etiopathogenesis of depression is not entirely understood. Several studies have investigated the role of inflammation in major depressive disorder. The present work aims to review the literature on the association between C-Reactive Protein (CRP) and depression. A systematic review was performed for the topics of 'CRP' and 'depression' using the PubMed database from inception to December 2021. Fifty-six studies were identified and included in the review. Evidence suggested the presence of dysregulation in the inflammation system in individuals with depression. In most studies, higher blood CRP levels were associated with greater symptom severity, a specific pattern of depressive symptoms, and a worse response to treatment. Moreover, about one-third of depressed patients showed a low-grade inflammatory state, suggesting the presence of a different major depressive disorder (MDD) subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis, which could benefit from monitoring of CRP levels and might potentially respond to anti-inflammatory treatments. This work provides robust evidence about the potential role of CRP and its blood levels in depressive disorders. These findings can be relevant to developing new therapeutic strategies and better understanding if CRP may be considered a valuable biomarker for depression.

69Systemic Inflammation at the Crossroad of Major Depressive Disorder and Comorbidities: A Narrative Review.PubMed

Erika Vitali, Nadia Cattane, Ilari D'Aprile, et al.
Int J Mol Sci. 2025 Sep 25;26(19):9382. doi: 10.3390/ijms26199382.
Major Depressive Disorder (MDD) represents a global challenge due to its high prevalence worldwide. Inflammation is the most extensively studied and plausible biological pathway involved in the onset of MDD. Individuals with MDD often exhibit low-grade inflammation, characterized by immune system dysregulation and activation of pro-inflammatory pathways. Elevated inflammation is also associated with a reduced response to antidepressant therapies, suggesting that targeting inflammation could represent a promising therapeutic approach for MDD. MDD frequently co-occurs with other pathological conditions, including cardiometabolic, autoimmune, and chronic pain disorders. These comorbidities further complicate MDD treatment and contribute to reduced antidepressant efficacy. Like MDD, these disorders are characterized by a strong inflammatory component, and several cytokines and pro-inflammatory mechanisms altered in MDD are also found in these comorbid conditions. This narrative review explores inflammation as a shared biological mechanism in MDD and its most frequent comorbidities, to provide a comprehensive understanding of the interplay between inflammation and these comorbid conditions. Persistent low-grade inflammation may help explain the high rate of bidirectional co-occurrence between MDD and its comorbidities. Moreover, it may represent a target for better understanding the molecular mechanisms driving this co-occurrence, potentially contributing to the development of tailored treatment and improving antidepressants response rates.

70Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study.PubMed

Luca Sforzini, Annamaria Cattaneo, Clarissa Ferrari, et al.
Transl Psychiatry. 2023 Jun 1;13(1):185. doi: 10.1038/s41398-023-02438-x.
Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case-control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1-3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.

71Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation.PubMed

Luca Sforzini, Moira Marizzoni, Chiara Bottanelli, et al.
Mol Psychiatry. 2025 Apr;30(4):1308-1318. doi: 10.1038/s41380-024-02736-w. Epub 2024 Sep 13.
Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 'not inflamed' (CRP < 1 mg/L), n = 31 with 'elevated CRP' (1-3 mg/L), and n = 35 with 'low-grade inflammation' (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1-3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this 'non-inflamed' depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual's trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.

72Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons.PubMed

Anna M Klawonn, Michael Fritz, Silvia Castany, et al.
Immunity. 2021 Feb 9;54(2):225-234.e6. doi: 10.1016/j.immuni.2020.12.016. Epub 2021 Jan 20.
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.

73Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress.PubMed

Li Liu, Jing Tang, Xin Liang, et al.
Mol Psychiatry. 2024 Jul;29(7):2031-2042. doi: 10.1038/s41380-024-02464-1. Epub 2024 Feb 15.
Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway.

74Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways.PubMed

Xiang Xu, Hu-Nan Piao, Fumie Aosai, et al.
Br J Pharmacol. 2020 Nov;177(22):5224-5245. doi: 10.1111/bph.15261. Epub 2020 Oct 19.
BACKGROUND AND PURPOSE: Arctigenin, a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies. EXPERIMENTAL APPROACH: The effects of chronic unpredictable mild stress (CUMS) on wild-type (WT) and TLR4 mice were examined. Antidepressant-like effects of arctigenin were tested using the CUMS-induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-α-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-α and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co-immunoprecipitation assays. KEY RESULTS: The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4 mice, compared with WT mice. Arctigenin exhibited antidepressant-like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF-α and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. CONCLUSIONS AND IMPLICATIONS: Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression.

75Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression.PubMed

Xian Xian, Li-Li Cai, Yang Li, et al.
J Nanobiotechnology. 2022 Mar 9;20(1):122. doi: 10.1186/s12951-022-01332-w.
BACKGROUND: Neuroinflammation is an important component mechanism in the development of depression. Exosomal transfer of MDD-associated microRNAs (miRNAs) from neurons to microglia might exacerbate neuronal cell inflammatory injury. RESULTS: By sequence identification, we found significantly higher miR-9-5p expression levels in serum exosomes from MDD patients than healthy control (HC) subjects. Then, in cultured cell model, we observed that BV2 microglial cells internalized PC12 neuron cell-derived exosomes while successfully transferring miR-9-5p. MiR-9-5p promoted M1 polarization in microglia and led to over releasing of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which exacerbated neurological damage. Furthermore, we identified suppressor of cytokine signaling 2 (SOCS2) as a direct target of miR-9-5p. Overexpression of miR-9-5p suppressed SOCS2 expression and reactivated SOCS2-repressed Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways. Consistently, we confirmed that adeno-associated virus (AAV)-mediated overexpression of miR-9-5p polarized microglia toward the M1 phenotype and exacerbated depressive symptoms in chronic unpredictable mild stress (CUMS) mouse mode. CONCLUSION: MiR-9-5p was transferred from neurons to microglia in an exosomal way, leading to M1 polarization of microglia and further neuronal injury. The expression and secretion of miR-9-5p might be novel therapeutic targets for MDD.

76Therapeutic targeting of STING-TBK1-IRF3 signalling ameliorates chronic stress induced depression-like behaviours by modulating neuroinflammation and microglia phagocytosis.PubMed

Na Duan, Yanpeng Zhang, Shuwen Tan, et al.
Neurobiol Dis. 2022 Jul;169:105739. doi: 10.1016/j.nbd.2022.105739. Epub 2022 Apr 22.
Stress is well known to contribute to the development of both neurological and psychiatric diseases. In the central nervous system, a role for STING (stimulator of interferon genes) in modulating immunological responses has been widely suggested, and this protein possesses both neurotoxic and neuroprotective properties. However, the potential role of the STING signalling pathway and the underlying regulatory mechanism in chronic stress have not been well established. In this study, C57BL/6 mice were subjected to intermittent restraint stress for 14 days (6 h/day), and sucrose preference, elevated plus maze, and tail suspension tests were performed by mice subjected to chronic restraint stress (RST). Here, we showed that RST mice displayed depression-like behaviours, accompanied by increased levels of proinflammatory cytokines in the brain. We also observed remarkably decreased levels of the pathway components STING, p-TBK1 (phospho-TANK-binding kinase-1), and p-IRF3 (phospho-interferon regulatory factor-3) in the hippocampus and the prefrontal cortex of RST mice. Significant reductions in STING fluorescence intensity were also observed in the hippocampus and the prefrontal cortex of RST mice. Next, fluorescently labelled latex beads, flow cytometry, and CD68-positive cell counts were utilized to evaluate the phagocytic abilities of microglia in vivo and in vitro. Importantly, our results first indicated that activation of the STING pathway by administration of the STING agonist 2'3-cGAMP enhanced microglial phagocytosis and suppressed the release of the proinflammatory cytokines TNF-α, IL-6, and IL-1β in the brains of RST mice, which further led to antidepressant effects. Based on the results of our study, the amelioration of stress-driven depression-like behaviours by activation of the STING pathway is associated with the suppression of neuroinflammation and enhanced phagocytosis.

77Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis.PubMed

Hong-Guang Zhang, Bin Wang, Yong Yang, et al.
Cell Res. 2022 Oct;32(10):897-913. doi: 10.1038/s41422-022-00689-9. Epub 2022 Jul 12.
Depression is a serious public-health issue. Recent reports have suggested higher susceptibility to viral infections in depressive patients. However, how depression affects antiviral innate immune signaling remains unknown. Here, we revealed a reduction in expression of Abelson helper integration site 1 (AHI1) in the peripheral blood mononuclear cells (PBMCs) and macrophages from the patients with major depressive disorder (MDD), which leads to attenuated antiviral immune response. We found that depression-related arginine vasopressin (AVP) induces reduction of AHI1 in macrophages. Further studies demonstrated that AHI1 is a critical stabilizer of basal type-I-interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2, while AHI1 reduction downregulates Tyk2 and IFN-I signaling activity in macrophages from both MDD patients and depression model mice. Interestingly, we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression, thus enhancing IFN-I antiviral defense in depression model mice. Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction, and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.

78Depressive Disorder, Anxiety Disorder and Chronic Pain: Multiple Manifestations of a Common Clinical and Pathophysiological Core.PubMed

Cesar A Arango-Dávila, Hernán G Rincón-Hoyos
Rev Colomb Psiquiatr (Engl Ed). 2018 Jan-Mar;47(1):46-55. doi: 10.1016/j.rcp.2016.10.007. Epub 2016 Dec 14.
INTRODUCTION: A high proportion of depressive disorders are accompanied by anxious manifestations, just as depression and anxiety often present with many painful manifestations, or conversely, painful manifestations cause or worsen depressive and anxious expressions. There is increasingly more evidence of the pathophysiological, and neurophysiological and technical imaging similarity of pain and depression. METHODS: Narrative review of the pathophysiological and clinical aspects of depression and chronic pain comorbidity. Research articles are included that emphasise the most relevant elements related to understanding the pathophysiology of both manifestations. RESULTS: The pathological origin, physiology and clinical approach to these disorders have been more clearly established with the latest advances in biochemical and cellular techniques, as well as the advent of imaging technologies. This information is systematised with comprehensive images and clinical pictures. CONCLUSIONS: The recognition that the polymorphism of inflammation-related genes generates susceptibility to depressive manifestations and may modify the response to antidepressant treatments establishes that the inflammatory response is not only an aetiopathogenic component of pain, but also of stress and depression. Likewise, the similarity in approach with images corroborates not only the structural, but the functional and pathophysiological analogy between depression and chronic pain. Knowledge of depression-anxiety-chronic pain comorbidity is essential in the search for effective therapeutic interventions.

79Neuroinflammatory Mechanisms Linking Pain and Depression.PubMed

Nikita N Burke, David P Finn, Michelle Roche
Mod Trends Pharmacopsychiatry. 2015;30:36-50. doi: 10.1159/000435931. Epub 2015 Sep 18.
Depression and chronic pain have been estimated to co-occur in up to 80% of patients suffering from these disorders, with this co-morbidity being more disabling and more expensive to both patients and society than either disorder alone. A number of neural substrates have been proposed to underlie this association; however, there has been increased interest and support for a role of neuroimmune and neuroinflammatory mechanisms as key players in this dyad. This chapter will provide an overview of the clinical and preclinical data supporting a role for neuroimmune alterations in depression-pain co-morbidity. We propose that such changes may impact on the functioning of key brain regions modulating emotional and nociceptive processing, thus resulting in the behavioural, psychological and physical symptoms observed in patients exhibiting depression and co-morbid pain.

80Patterns and prevalence of psychiatric morbidity among individuals with rheumatoid arthritis.PubMed

Ajaz Kariem Khan, Junaid Nabi, Ashaq Hussain Parrey, et al.
Reumatologia. 2024;62(2):115-120. doi: 10.5114/reum/186975. Epub 2024 Apr 30.
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints, causing inflammation, pain, and potential joint damage. Patients with RA are at high risk of developing psychiatric morbidity; it is important to recognize these psychiatric manifestations. The relationship between psychiatric symptoms and RA is complex and can involve various factors, including the impact of chronic pain, inflammation, medications, and the overall burden of managing a chronic illness.Aim of the study was to systematically investigate and analyze the patterns and prevalence of psychiatric morbidity among individuals diagnosed with RA, with the aim of identifying common mental health conditions, understanding the interplay between RA and psychiatric disorders, and providing valuable insights for improved holistic patient care. MATERIAL AND METHODS: This was a prospective, observational cross-sectional study conducted over a period of three years in patients with RA. Psychiatric morbidity was assessed using International Classification of Diseases-10 criteria and Mini-Plus by dedicated psychiatrists. The diagnosis of RA was confirmed using the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) diagnostic criteria for RA and the disease activity was calculated by Disease Activity Score with 28-joint count (DAS28) using the calculator from the RheumaHelper application. The data were analyzed using SPSS, version 23.0. RESULTS: A total of 1,000 patients with RA were included in this study. Nearly two-thirds of the patients were female (64.8%). The majority of patients belonged to the age group of 41 to 54 years. Total 47.5% of the patients were unemployed, 27.0% were salaried, 19.0% were businessman, while 6.5% of the patients were students. More than half of the patients (53.2%) had moderate disease activity. Major depressive disorder was the most commonly observed comorbidity (41.0%), followed by somatoform disorder (28.5%), and generalized anxiety disorder was found in 13.5%. No psychiatric manifestations were found in 17% of studied individuals. CONCLUSIONS: Psychiatric morbidity is associated with RA and there is a need for psychiatric services to be made available to these patients.

81Human corticotropin releasing hormone: clinical studies in patients with affective disorders, alcoholism, panic disorder and in normal controls.PubMed

U von Bardeleben, F Holsboer
Prog Neuropsychopharmacol Biol Psychiatry. 1988;12 Suppl:S165-87. doi: 10.1016/0278-5846(88)90079-6.
1. The 41 amino acid peptide human corticotropin releasing hormone (h-CRH) and its ovine analogue o-CRH are regulators of proopiomelanocortin (POMC) derived neuropeptides and neurosteroids of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis such as beta-endorphin, corticotropin (ACTH) and corticosteroids modulating concomitantly hormonal and behavioral systems in animal and man, e.g. adaptation to stress. 2. Challenge tests employing h-CRH stimulation with or without different kinds of pretreatment in affective disorders, alcoholism, and panic disorder demonstrate LHPA alterations that are induced by dysregulations in the limbic area. In depression, the enhanced secretory activity of pituitary corticotrophs or altered feedback regulation is compatible with endogenous CRH hypersecretion followed by enhanced production of proopiomelanocortin whose fragments activate synthesis and release of adrenal corticosteroids. These effects are accompanied by development of a functional hyperplasia of the adrenocortex and/or down-regulation of pituitary CRH-receptors and/or reduced negative feed back capacity of limbic glucocorticoid receptor containing neurones particularly in the hippocampus. Similar disturbances are found in hypercortisolemic patients withdrawn from alcohol and are less pronounced in patients with panic disorder. 3. Repetitive h-CRH administration to normal controls induces sleep-EEG and neuroendocrine effects resembling those in depression. 4. Adrenocortical hormones act back on neurotransmitter/receptor sites of brain systems relevant for neuropharmacoloy (e.g. GABA receptor activity in anxiety disorders and affective disorders). 5. The neuroendocrine approach to the LHPA axis is of value to uncover several aspects of pathology underlying various psychiatric diseases.

82The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders.PubMed

Emilija Knezevic, Katarina Nenic, Vladislav Milanovic, et al.
Cells. 2023 Nov 29;12(23):2726. doi: 10.3390/cells12232726.
Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer's and Parkinson's, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

83The HPA Axis as Target for Depression.PubMed

Andreas Menke
Curr Neuropharmacol. 2024;22(5):904-915. doi: 10.2174/1570159X21666230811141557.
Major depressive disorder (MDD) is a stress-related mental disorder with a lifetime prevalence of 20% and, thus, is one of the most prevalent mental health disorders worldwide. Many studies with a large number of patients support the notion that abnormalities of the hypothalamus-pituitaryadrenal (HPA) axis are crucial for the development of MDD. Therefore, a number of strategies and drugs have been investigated to target different components of the HPA axis: 1) corticotrophinreleasing hormone (CRH) 1 receptor antagonists; 2) vasopressin V receptor antagonists, 3) glucocorticoid receptor antagonists, and 4) FKBP5 antagonists. Until now, V receptor antagonists and GR antagonists have provided the most promising results. Preclinical data also support antagonists of FKBP5, which seem to be partly responsible for the effects exerted by ketamine. However, as HPA axis alterations occur only in a subset of patients, specific treatment approaches that target only single components of the HPA axis will be effective only in this subset of patients. Companion tests that measure the function of the HPA axis and identify patients with an impaired HPA axis, such as the dexamethasone-corticotrophin-releasing hormone (dex-CRH) test or the molecular dexamethasonesuppression (mDST) test, may match the patient with an effective treatment to enable patient-tailored treatments in terms of a precision medicine approach.

84The biologic effects of grounding the human body during sleep as measured by cortisol levels and subjective reporting of sleep, pain, and stress.PubMed

Maurice Ghaly, Dale Teplitz
J Altern Complement Med. 2004 Oct;10(5):767-76. doi: 10.1089/acm.2004.10.767.
OBJECTIVES: Diurnal cortisol secretion levels were measured and circadian cortisol profiles were evaluated in a pilot study conducted to test the hypothesis that grounding the human body to earth during sleep will result in quantifiable changes in cortisol. It was also hypothesized that grounding the human body would result in changes in sleep, pain, and stress (anxiety, depression, irritability), as measured by subjective reporting. SUBJECTS AND INTERVENTIONS: Twelve (12) subjects with complaints of sleep dysfunction, pain, and stress were grounded to earth during sleep for 8 weeks in their own beds using a conductive mattress pad. Saliva tests were administered to establish pregrounding baseline cortisol levels. Levels were obtained at 4-hour intervals for a 24-hour period to determine the circadian cortisol profile. Cortisol testing was repeated at week 6. Subjective symptoms of sleep dysfunction, pain, and stress were reported daily throughout the 8-week test period. RESULTS: Measurable improvements in diurnal cortisol profiles were observed, with cortisol levels significantly reduced during night-time sleep. Subjects' 24-hour circadian cortisol profiles showed a trend toward normalization. Subjectively reported symptoms, including sleep dysfunction, pain, and stress, were reduced or eliminated in nearly all subjects. CONCLUSIONS: Results indicate that grounding the human body to earth ("earthing") during sleep reduces night-time levels of cortisol and resynchronizes cortisol hormone secretion more in alignment with the natural 24-hour circadian rhythm profile. Changes were most apparent in females. Furthermore, subjective reporting indicates that grounding the human body to earth during sleep improves sleep and reduces pain and stress.

85Human studies on hypothalamo-pituitary-adrenal (HPA) axis.PubMed

Kamani Liyanarachchi, Richard Ross, Miguel Debono
Best Pract Res Clin Endocrinol Metab. 2017 Oct;31(5):459-473. doi: 10.1016/j.beem.2017.10.011. Epub 2017 Nov 2.
The daily rhythm of the hypothalamo-pituitary-adrenal (HPA) axis is regulated by the central clock in the suprachiasmatic nucleus. Cortisol, a glucocorticoid, acts as a secondary messenger between the central clock and the peripheral tissues. Changes in clock time, as seen in shift workers, alters the HPA axis and results in metabolic disturbances associated with ill health. Depression, anorexia nervosa and obstructive sleep apnoea, are associated with cortisol rhythm phase shifts and increased cortisol exposure. Higher nocturnal cortisol exposure is observed in patients with Cushing's syndrome and adrenal incidentalomas with autonomous cortisol secretion and is associated with insulin resistance, and increased cardiovascular risk and mortality. A decrease in cortisol rhythm amplitude is seen in adrenal insufficiency, and despite replacement, patients have an impaired quality of life and increased mortality. Research on cortisol replacement has focused on replacing the cortisol daily rhythm by subcutaneous hydrocortisone infusions and oral modified release hydrocortisone formulations with the aim of improving disease control and quality of life.

86The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies.PubMed

M J Owens, C B Nemeroff
Ciba Found Symp. 1993;172:296-308; discussion 308-16. doi: 10.1002/9780470514368.ch15.
The unique distribution of corticotropin-releasing factor (CRF) and its receptors within the central nervous system, its pre-eminent role in mediating the endocrine, behavioural, autonomic and immunological effects of stress and its potent effects after direct administration into the CNS all support the hypothesis that alterations in CRF neuronal systems contribute to the pathophysiology of depression and certain anxiety disorders. This report summarizes a series of preclinical and clinical investigations which have sought to test the hypothesis that CRF-containing neurons show alterations in depression and anxiety, and that drugs used to treat these disorders alter CRF neuronal circuits. Direct injection of CRF into the locus ceruleus or nearby parabrachial nucleus evokes an anxiogenic response. Stress increases CRF concentrations in the locus ceruleus, whereas alprazolam, a benzodiazepine anxiolytic, decreases the concentration of the peptide in the same area. Clinical studies reveal that drug-free depressed patients show: (1) hyperactivity of the hypothalamo-pituitary-adrenal axis; (2) increased CRF concentrations in the cerebrospinal fluid; (3) a blunted release of ACTH in response to CRF; (4) a reduced density of CRF receptors in the frontal cortex; (5) pituitary and adrenal gland hypertrophy. These findings are all concordant with hypersecretion of CRF from hypothalamic and extrahypothalamic CRF neurons in depression.

87Role of CRF receptor signaling in stress vulnerability, anxiety, and depression.PubMed

Richard L Hauger, Victoria Risbrough, Robert H Oakley, et al.
Ann N Y Acad Sci. 2009 Oct;1179:120-43. doi: 10.1111/j.1749-6632.2009.05011.x.
Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF-related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF(1) receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF(1) receptors become rapidly desensitized by G protein-coupled receptor kinase (GRK) and beta-arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress-induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and beta-arrestin binding can shift a G protein-coupled receptor (GPCR) to signal selectively via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) or Akt pathways independent of G proteins. Also, Epac-dependent CRF(1) receptor signaling via the ERK-MAPK pathway has been found to potentiate brain-derived neurotrophic factor (BDNF)-stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and beta-arrestin function may be involved in the pathophysiology of stress-induced anxiety and depression.

88Hippocampal serotonergic system is involved in anxiety-like behavior induced by corticotropin-releasing factor.PubMed

Yoshifumi Kagamiishi, Tsuneyuki Yamamoto, Shigenori Watanabe
Brain Res. 2003 Nov 21;991(1-2):212-21. doi: 10.1016/j.brainres.2003.08.021.
To clarify the interaction between anxiety-like behavior produced by corticotropin-releasing factor (CRF) and the 5-HT system, we investigated the effects of intracerebroventricular (i.c.v.) administration of CRF on an elevated plus-maze performance as indices of anxiety, measuring extracellular levels of 5-HT in the ventral hippocampus using an in vivo brain dialysis method in rats. The time spent in the open arms of the maze and the number of open arm entries were decreased in a dose-dependent manner by the administration of CRF (0.3-1.0 microg/rat). These effects of CRF were prevented by pretreatment with a 5-HT(1A) receptor agonist, 8-OH-DPAT (0.5 mg/kg, s.c.). In biochemical studies, CRF increased 5-HT release about 150-250% above baseline in the ventral hippocampus and this elevation was significantly inhibited by a CRF receptor antagonist, alpha-Helical CRF(9-41) (50 mug/rat), and 5-HT(1A) receptor agonist, 8-OH-DPAT (0.5 mg/kg, s.c.). These results suggested that the anxiety-like effect produced by CRF may have involved increased 5-HT transmission in the ventral hippocampus. Taken with the evidence for hypersecretion of CRF in patients with depression and anxiety-related disorders, our findings lead to the intriguing hypothesis that interaction between CRF and 5-HT, especially in the ventral hippocampus, plays a role in the etiology of affective and anxiety disorders.

89The etiology of poststroke-depression: a hypothesis involving HPA axis.PubMed

Lin Zhou, Tian Wang, Yawen Yu, et al.
Biomed Pharmacother. 2022 Jul;151:113146. doi: 10.1016/j.biopha.2022.113146. Epub 2022 May 26.
Approximately, one in three ischemic stroke survivors suffered from depression, namely, post-stroke depression (PSD). PSD affects functional rehabilitation and may lead to poor quality of life of patients. There are numerous explanations about the etiologies of PSD. Here, we speculated that PSD are likely to be the result of specific changes in brain pathology. We hypothesized that the stroke-induced hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis plays an important role in PSD. Stroke initiates a complex sequence of events in neuroendocrine system including HPA axis. The HPA axis is involved in the pathophysiology of depression, especially, the overactivity of the HPA axis occurs in major depressive disorder. This review summarizes the possible etiologies of PSD, focusing on the stroke-induced activation of HPA axis, mainly including the stress followed by severe brain damage and the proinflammatory cytokines release. The role of hyperactive of HPA axis in PSD was discussed in detail, which includes the role of high level corticotropin-releasing hormone in PSD, the effects of glucocorticoids on the alterations in specific brain structures, the expression of enzymes, excitotoxicity, the change in intestinal permeability, and the activation of microglia. The relationship between neuroendocrine regulation and inflammation was also described. Finally, the therapy of PSD by regulating HPA axis, neuroendocrine, and immunity was discussed briefly. Nevertheless, the change of HPA axis and the occurring of PSD maybe interact and promote on each other, and future investigations should explore this hypothesis in more depth.

90Postpartum depression: Etiology, treatment and consequences for maternal care.PubMed

Susanne Brummelte, Liisa A M Galea
Horm Behav. 2016 Jan;77:153-66. doi: 10.1016/j.yhbeh.2015.08.008. Epub 2015 Aug 28.
This article is part of a Special Issue "Parental Care". Pregnancy and postpartum are associated with dramatic alterations in steroid and peptide hormones which alter the mothers' hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes. Dysregulations in these endocrine axes are related to mood disorders and as such it should not come as a major surprise that pregnancy and the postpartum period can have profound effects on maternal mood. Indeed, pregnancy and postpartum are associated with an increased risk for developing depressive symptoms in women. Postpartum depression affects approximately 10-15% of women and impairs mother-infant interactions that in turn are important for child development. Maternal attachment, sensitivity and parenting style are essential for a healthy maturation of an infant's social, cognitive and behavioral skills and depressed mothers often display less attachment, sensitivity and more harsh or disrupted parenting behaviors, which may contribute to reports of adverse child outcomes in children of depressed mothers. Here we review, in honor of the "father of motherhood", Jay Rosenblatt, the literature on postnatal depression in the mother and its effect on mother-infant interactions. We will cover clinical and pre-clinical findings highlighting putative neurobiological mechanisms underlying postpartum depression and how they relate to maternal behaviors and infant outcome. We also review animal models that investigate the neurobiology of maternal mood and disrupted maternal care. In particular, we discuss the implications of endogenous and exogenous manipulations of glucocorticoids on maternal care and mood. Lastly we discuss interventions during gestation and postpartum that may improve maternal symptoms and behavior and thus may alter developmental outcome of the offspring.

91Biological aspects of postpartum depression.PubMed

Alkistis Skalkidou, Charlotte Hellgren, Erika Comasco, et al.
Womens Health (Lond). 2012 Nov;8(6):659-72. doi: 10.2217/whe.12.55.
In comparison with the vast epidemiological literature on postpartum depression (PPD), relatively few studies have examined the biological aspects of the disorder. However, research into the biological mechanisms of PPD is a challenging task, as normal pregnancy and the postpartum period cause adaptive endocrine changes, which would otherwise be considered pathological in nonpregnant women. This review focuses on the adaptive changes of childbearing and nursing, which ultimately may put women at increased risk of PPD. In light of the normal physiology, the authors also attempt to describe the current evidence of the biological changes associated with the development of depression in the postpartum period, including ovarian steroids, the hypothalamic-pituitary-adrenal axis, the serotonergic neurotransmitter system, the thyroid system and inflammatory markers. In addition, current knowledge on candidate genes associated with PPD is reviewed.

92[Oxytocin and postpartum depression].PubMed

C Cardaillac, C Rua, E G Simon, et al.
J Gynecol Obstet Biol Reprod (Paris). 2016 Oct;45(8):786-795. doi: 10.1016/j.jgyn.2016.05.002. Epub 2016 Jun 14.
INTRODUCTION: Postpartum depression (PPD) is prevalent (about 10%) with a major impact on the mother and child health. At the hormonal level, poor regulation of oxytocin rate has a key role in depression. Recently, oxytocin has been used on psychiatric therapy, intranasal or intravenously, particularly in mood disorders. But, in obstetrics, this molecule is administered during childbirth. The objective of this study was to determine if intravenous administration of oxytocin could influence thymic state of the mother in the postpartum period. METHODS: Literature review, after consultation of Pubmed and Sciencedirect databases, with the following keywords: oxytocin, postpartum depression, pregnancy, social behavior. RESULTS: The effects of oxytocin in the PPD are part of a multifactorial mechanism (hormonal and social) that influences the hormonal effects of oxytocin. Oxytocin use in therapeutic was able to give conclusive results in psychiatry, the way and the optimal method of administration are not known. PPD is associated with administrated oxytocin during labour. Physiopathology remains unknown. CONCLUSION: It is possible that oxytocin administered during childbirth is related with the onset or worsening of the PPD without defining if it's a cause or a consequence.

93Peripartum effects of synthetic oxytocin: The good, the bad, and the unknown.PubMed

Mahmoud Rashidi, Eduard Maier, Sharon Dekel, et al.
Neurosci Biobehav Rev. 2022 Oct;141:104859. doi: 10.1016/j.neubiorev.2022.104859. Epub 2022 Sep 7.
The first clinical applications of oxytocin (OT) were in obstetrics as a hormone to start and speed up labor and to control postpartum hemorrhage. Discoveries in the 1960s and 1970s revealed that the effects of OT are not limited to its peripheral actions around birth and milk ejection. Indeed, OT also acts as a neuromodulator in the brain affecting fear memory, social attachment, and other forms of social behaviors. The peripheral and central effects of OT have been separately subject to extensive scrutiny. However, the effects of peripheral OT-particularly in the form of administration of synthetic OT (synOT) around birth-on the central nervous system are surprisingly understudied. Here, we provide a narrative review of the current evidence, suggest putative mechanisms of synOT action, and provide new directions and hypotheses for future studies to bridge the gaps between neuroscience, obstetrics, and psychiatry.

94Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.PubMed

Aysu Okbay, Bart M L Baselmans, Jan-Emmanuel De Neve, et al.
Nat Genet. 2016 Jun;48(6):624-33. doi: 10.1038/ng.3552. Epub 2016 Apr 18.
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

95Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.PubMed

Mats Nagel, Philip R Jansen, Sven Stringer, et al.
Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
Neuroticism is an important risk factor for psychiatric traits, including depression, anxiety, and schizophrenia. At the time of analysis, previous genome-wide association studies (GWAS) reported 16 genomic loci associated to neuroticism. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 × 10), medium spiny neurons (P = 4.23 × 10), and serotonergic neurons (P = 1.37 × 10). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 × 10), behavioral response to cocaine processes (P = 1.84 × 10), and axon part (P = 5.26 × 10). We show that neuroticism's genetic signal partly originates in two genetically distinguishable subclusters ('depressed affect' and 'worry'), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.

96Stress-reactive rumination, negative cognitive style, and stressors in relationship to depressive symptoms in non-clinical youth.PubMed

Lea Rood, Jeffrey Roelofs, Susan M Bögels, et al.
J Youth Adolesc. 2012 Apr;41(4):414-25. doi: 10.1007/s10964-011-9657-3. Epub 2011 Mar 31.
The role of cognitive vulnerability in the development of depressive symptoms in youth might depend on age and gender. The current study examined cognitive vulnerability models in relationship to depressive symptoms from a developmental perspective. For that purpose, 805 youth (aged 10-18, 59.9% female) completed self-report measures. Stress-reactive rumination was strongly related to depressive symptoms. Negative cognitive style (i.e., tendency to make negative inferences) in the domains of achievement and appearance was more strongly and consistently related to depressive symptoms in girls compared to boys. Negative cognitive style in the interpersonal domain was positively related to depressive symptoms in both girls and boys, except in early adolescent girls reporting few stressors. To conclude, the cognitive vulnerability-stress interaction may be moderated by the combination of age and gender in youth, which may explain inconsistent findings so far. Current findings highlight the importance of taking into account domain specifity when examining models of depression in youth.

97Cognitive and Interpersonal Vulnerabilities to Adolescent Depression: Classification of Risk Profiles for a Personalized Prevention Approach.PubMed

Benjamin L Hankin, Jami F Young, Robert Gallop, et al.
J Abnorm Child Psychol. 2018 Oct;46(7):1521-1533. doi: 10.1007/s10802-018-0401-2.
Despite interest in psychosocial vulnerabilities to depression, little is known about reliable and valid individualized risk profiles that can be used to match individuals to evidence-based interventions for depression. This study investigated well-established cognitive and interpersonal vulnerabilities to depression among youth to discern an evidence-based risk classification approach which is being used in a personalized depression prevention randomized clinical trial. Data were drawn from a general community sample of adolescents (N = 467; ages 10-16, mean 13.14, SD = 1.62; 57% females) who were followed prospectively for 3 years. Youth completed measures of cognitive (negative cognitive style, dysfunctional attitudes, rumination) and interpersonal (support and conflict with peers and parents, excessive reassurance seeking, social competence, co-rumination) risks to depression, and then were followed longitudinally for onset of depression. Principal axis factor analyses showed that three latent factors--cognitive vulnerability, interpersonal support, and interpersonal conflict--optimally represented the structure of these risk factors. Clinically practical and meaningful cutoffs, based on tertile cut-off scores on cognitive and interpersonal risk measures, were used to categorize youth into relatively balanced high and low cognitive and interpersonal risk groups. These risk classification groups exhibited validity (AUC > 0.70) by predicting prospective onsets of depressive episodes at 18-months follow-ups. These findings demonstrate a reliable and valid approach to synthesize psychosocial vulnerabilities to depression, specifically cognitive and interpersonal risks. Results are discussed in terms of using these risk classifications profiles to test personalized prevention of depression during adolescence.

98Cognitive vulnerabilities as mediators between emotional abuse and depressive symptoms.PubMed

Patricia Padilla Paredes, Esther Calvete
J Abnorm Child Psychol. 2014;42(5):743-53. doi: 10.1007/s10802-013-9828-7.
This study tested whether childhood parental emotional abuse and peer emotional bullying serve as antecedents of depression in adolescence and identified the cognitive mechanisms involved in this process. It was hypothesized that the experience of emotional abuse would predict depressive symptoms via development of rumination and negative inferences. A 3-wave longitudinal study was carried out with 998 adolescents (471 girls and 526 boys) between 13 and 17 years of age. Results showed that emotional abuse by parents and peers at Time 1 predicted a worsening of several cognitive vulnerabilities at Time 2. In addition, brooding mediated between the experiences of abuse and the increase of depressive symptoms at Time 3. Thus, findings suggest that the experiences of childhood emotional abuse by parents and peers serve as antecedents to develop a negative cognitive style, vulnerability that, once developed, is a risk factor for the onset of depressive symptoms in adolescence.

99Reflecting on rumination: Consequences, causes, mechanisms and treatment of rumination.PubMed

Edward R Watkins, Henrietta Roberts
Behav Res Ther. 2020 Apr;127:103573. doi: 10.1016/j.brat.2020.103573. Epub 2020 Jan 31.
We review research showing that rumination has multiple negative consequences: (a) exacerbating psychopathology by magnifying and prolonging negative mood states, interfering with problem-solving and instrumental behaviour and reducing sensitivity to changing contingencies; (b) acting as a transdiagnostic mental health vulnerability impacting anxiety, depression, psychosis, insomnia, and impulsive behaviours; (c) interfering with therapy and limiting the efficacy of psychological interventions; (d) exacerbating and maintaining physiological stress responses. The mechanisms underlying rumination are examined, and a model (H-EX-A-GO-N - Habit development, EXecutive control, Abstract processing, GOal discrepancies, Negative bias) is proposed to account for the onset and maintenance of rumination. H-EX-A-GO-N outlines how rumination results from dwelling on problematic goals developing into a learnt habit that involves the tendency to process negative information in an abstract way, particularly in the context of poor executive control and negative information-processing biases. These proximal factors integrate experimental evidence to provide a partial answer to the critical question of what maintains rumination. They constitute a pathway by which more distal biological and environmental factors increase the likelihood of rumination developing. Treatments for rumination are reviewed, with preliminary trials suggesting that psychological interventions designed to specifically target these mechanisms may be effective at reducing rumination.

100Emotion Regulation Strategies in Depressive and Anxiety Symptoms in Youth: A Meta-Analytic Review.PubMed

Johanna Özlem Schäfer, Eva Naumann, Emily Alexandra Holmes, et al.
J Youth Adolesc. 2017 Feb;46(2):261-276. doi: 10.1007/s10964-016-0585-0. Epub 2016 Oct 12.
The role of emotion regulation in subclinical symptoms of mental disorders in adolescence is not yet well understood. This meta-analytic review examines the relationship between the habitual use of prominent adaptive emotion regulation strategies (cognitive reappraisal, problem solving, and acceptance) and maladaptive emotion regulation strategies (avoidance, suppression, and rumination) with depressive and anxiety symptoms in adolescence. Analyzing 68 effect sizes from 35 studies, we calculated overall outcomes across depressive and anxiety symptoms as well as psychopathology-specific outcomes. Age was examined as a continuous moderator via meta-regression models. The results from random effects analyses revealed that the habitual use of all emotion regulation strategies was significantly related to depressive and anxiety symptoms overall, with the adaptive emotion regulation strategies showing negative associations (i.e., less symptoms) with depressive and anxiety symptoms whereas the maladaptive emotion regulation strategies showed positive associations (i.e., more symptoms). A less frequent use of adaptive and a more frequent use of maladaptive emotion regulation strategies were associated with depressive and anxiety symptoms comparably in the respective directions. Regarding the psychopathology-specific outcomes, depressive and anxiety symptoms displayed similar patterns across emotion regulation strategies showing the strongest negative associations with acceptance, and strongest positive associations with avoidance and rumination. The findings underscore the relevance of adaptive and also maladaptive emotion regulation strategies in depressive and anxiety symptoms in youth, and highlight the need to further investigate the patterns of emotion regulation as a potential transdiagnostic factor.

101Rumination and the default mode network: Meta-analysis of brain imaging studies and implications for depression.PubMed

Hui-Xia Zhou, Xiao Chen, Yang-Qian Shen, et al.
Neuroimage. 2020 Feb 1;206:116287. doi: 10.1016/j.neuroimage.2019.116287. Epub 2019 Oct 23.
Rumination is strongly and consistently correlated with depression. Although multiple studies have explored the neural correlates of rumination, findings have been inconsistent and the mechanisms underlying rumination remain elusive. Functional brain imaging studies have identified areas in the default mode network (DMN) that appear to be critically involved in ruminative processes. However, a meta-analysis to synthesize the findings of brain regions underlying rumination is currently lacking. Here, we conducted a meta-analysis consisting of experimental tasks that investigate rumination by using Signed Differential Mapping of 14 fMRI studies comprising 286 healthy participants. Furthermore, rather than treat the DMN as a unitary network, we examined the contribution of three DMN subsystems to rumination. Results confirm the suspected association between rumination and DMN activation, specifically implicating the DMN core regions and the dorsal medial prefrontal cortex subsystem. Based on these findings, we suggest a hypothesis of how DMN regions support rumination and present the implications of this model for treating major depressive disorder characterized by rumination.

102Resilience and mental health nursing: An integrative review of international literature.PubMed

Kim Foster, Michael Roche, Cynthia Delgado, et al.
Int J Ment Health Nurs. 2019 Feb;28(1):71-85. doi: 10.1111/inm.12548. Epub 2018 Oct 7.
Mental health nurses work in challenging and potentially high stress settings. Stressors can occur in the context of consumer, family, and/or staff relationships, as well as the work environment and organization. The cumulative effects of stress and professional challenges can lead to harmful impacts for mental health nurses including burnout and poorer physical and mental health. Resilience involves a process of positive adaptation to stress and adversity. The aims of this integrative review were to examine understandings and perspectives on resilience, and explore and synthesize the state of knowledge on resilience in mental health nursing. Following systematic search processes, screening, and data extraction, 12 articles were included. Constant comparative analysis and synthesis of the data resulted in two key categories: Theoretical concepts of resilience and Knowledge on mental health nurses' resilience. In mental health nursing, resilience has been variously constructed as an individual ability, collective capacity, or as an interactive person-environment process. Resilience was most often reported as low-moderate, with positive correlations with hardiness, self-esteem, life and job satisfaction, and negative correlations with depression and burnout. A resilience programme improved mental health nurses' coping self-efficacy and capacity to regulate thoughts and emotions and developed their resilient practice. Use of contemporary resilience definitions will inform more consistent investigation and progressively scaffold knowledge of this emergent construct in mental health nursing. Future research on the implementation of resilience programmes and resilience-building strategies for mental health nurses at the individual, work unit, and organizational levels is needed.

103Resilience, depression and self-efficacy among Brazilian nursing professionals during the COVID-19 pandemic.PubMed

Laelson Rochelle Milanês Sousa, Pedro Henrique Tertuliano Leoni, Raphael Augusto Gir de Carvalho, et al.
Cien Saude Colet. 2023 Oct;28(10):2941-2950. doi: 10.1590/1413-812320232810.09852023. Epub 2023 Jun 26.
This aim of this study was to analyze levels of resilience, depression and self-efficacy among Brazilian nursing professionals during the COVID-19 pandemic. We conducted an analytical cross-sectional study between October and December 2020. Student's t test, analysis of variance and multiple linear regression were used to investigate the impact of two main factors (Resilience and Self-efficacy) on depression. A total of 8,792 nursing professionals participated in the study; 5,124 (58.8%) had low levels of resilience. The mean overall score for Depression was 0.74, ranging from 0.59 to 0.80, while the mean overall score for Self-efficacy was 0.68, ranging from 0.56 to 0.80. The variable that had the strongest impact on depression levels was Resilience, explaining 6.6% of the outcome (p < 0.001, AdjustedR2 = 0.066). In general, respondents had low levels of resilience and self-efficacy and showed high mean depression scores. Level of resilience had an impact on depression. The findings reveal an urgent need for actions to promote the psychological health of nursing professionals working in crisis situations such as pandemics.

104Factors related to the resilience and mental health of adult cancer patients: a systematic review.PubMed

Saori Tamura, Kumi Suzuki, Yuri Ito, et al.
Support Care Cancer. 2021 Jul;29(7):3471-3486. doi: 10.1007/s00520-020-05943-7. Epub 2021 Jan 29.
PURPOSE: It has been reported that maintaining the mental health of cancer patients is a critically important issue, and that resilience is related to mental health. This study conducted a systematic literature review in order to fully understand the relationships between resilience and anxiety, depression, and quality of life (QOL) in adult cancer patients, as well as identify factors associated with resilience. METHODS: The PubMed, CINAHL, Psychology Database, and ICHUSHI Web databases were searched for articles related to resilience in cancer patients published between 2014 and 2019 using the keywords "cancer" and "resilience," connected with "and." The extracted articles that met inclusion criteria were organized using a matrix. To understand the resilience status of adult cancer patients, meta-analyses were performed using resilience scores measured with the most commonly used resilience scale, Connor-Davidson Resilience Scale 25. RESULTS: Thirty-nine articles were included in the analysis. A higher resilience score is associated with lower anxiety and depression scores and higher QOL scores. Factors related to resilience include personal factors such as age and gender, disease-related factors such as the presence or absence and severity of physical symptoms, and internal factors such as self-efficacy and hopefulness. CONCLUSIONS: It was found that it is important for cancer patients to improve resilience to maintain mental health and QOL. The findings suggest that providing interventions for factors that will reduce resilience will provide support for patients with cancer.

105Specific effects of cumulative childhood trauma on suicidality among youths.PubMed

Qiaoqing Zheng, Yi Feng, Jinmei Du, et al.
J Affect Disord. 2024 Aug 1;358:260-269. doi: 10.1016/j.jad.2024.05.027. Epub 2024 May 3.
BACKGROUND: Suicidality was very high among individuals who suffered from childhood trauma. The distribution of cumulative childhood trauma among youths remains unclear, as well as the specific effects of cumulative childhood trauma on suicidality. This study attempted to explore the distribution of cumulative childhood trauma and examine the specific effects of cumulative childhood trauma on suicidality. METHODS: A cross-sectional design was employed in this study, with 117,769 college students recruited from 63 universities in Jilin Province, China. All variables were measured by corresponding self-report questionnaires. The Venn diagram was used to represent the distribution of single and cumulative childhood trauma. ANOVA and chi-square tests were conducted to identify the high-risk suicide groups. Multiple linear regression analysis was performed to examine risk factors for suicidality for overlapping subtypes. RESULTS: 27,671 (23.5%) participants reported suffering from childhood trauma, of which 49.5% were male (M = 19.59, SD = 1.76). The "physical neglect" group accounted for the largest proportion (31.5%). Suicidality was the highest in the "overlap of childhood neglect, emotional abuse, and physical abuse" group (2.0%). Depression, obsessive-compulsive disorder, and post-traumatic stress disorder were common risk factors for suicidality. LIMITATIONS: This study was limited by cross-sectional studies and self-report bias. CONCLUSIONS: The childhood trauma subtype group with the largest proportion was not necessarily the highest suicidality. Both the largest group and the highest-risk suicide group require special attention to their respective risk factors.

106Stress and the Development of Cognitive Vulnerabilities to Depression Explain Sex Differences in Depressive Symptoms during Adolescence.PubMed

Jessica L Hamilton, Jonathan P Stange, Lyn Y Abramson, et al.
Clin Psychol Sci. 2015 Sep 1;3(5):702-714. doi: 10.1177/2167702614545479. Epub 2014 Oct 2.
Although cognitive vulnerabilities to depression have received considerable empirical support, little research has evaluated the differential development of cognitive vulnerabilities in adolescent girls and boys. The current study examined the role of stressful life events, as well as sex differences in reactivity and exposure to stress, in the development of negative cognitive style and rumination in a multi-wave study of 382 adolescents. Path analyses indicated that interpersonal dependent stress predicted higher prospective levels of negative cognitive styles and rumination. Additionally, girls' greater exposure to interpersonal dependent stress explained their higher levels of rumination, which accounted for girls' higher levels of depressive symptoms than boys. These findings suggest that interpersonal dependent stress is a significant risk factor for the formation of cognitive vulnerabilities to depression during adolescence, and that the sex difference in depressive symptoms may result from girls' greater exposure to interpersonal dependent stress and ruminative response style than boys.

107The Effects of Rumination and Depressive Symptoms on the Prediction of Negative Attributional Style Among College Students.PubMed

Cola S L Lo, Samuel M Y Ho, Steven D Hollon
Cognit Ther Res. 2010 Apr;34(2):116-123. doi: 10.1007/s10608-009-9233-2. Epub 2009 Feb 3.
Research on cognitive vulnerability to depression has identified negative cognitive style and rumination as distinct risk factors for depression but how rumination would influence negative cognitive style remains unclear. The present study investigated the relationship between rumination and negative attributional style and specifically tested the potential moderating effect of depressive symptoms and processing mode during rumination on activating negative attributional style. After completing the baseline measures of depressive symptoms, dysphoric affect, and negative attributional style, participants were randomly assigned to three experimental conditions: analytical self-focus, experiential self-focus, and distraction, in which the degree of self-focus and mode of processing were manipulated. A second set of mood and cognitive measures was administered afterwards. Results showed that a stronger positive relationship between negative attributional style and level of depressive symptoms was found in the analytical self-focus condition, relative to the experiential and distraction conditions. This finding suggested that processing mode in rumination interacted with depressive symptoms to predict negative attributional style.

108Association between social support and postpartum depression.PubMed

Hahyeon Cho, Kyeongmin Lee, Eunji Choi, et al.
Sci Rep. 2022 Feb 24;12(1):3128. doi: 10.1038/s41598-022-07248-7.
Postpartum depression is common; however, little is known about its relationship to social support and postpartum depression. This study examined the association between them among South Korean women within one year of childbirth. This study was based on the 2016 Korean Study of Women's Health-Related Issues (K-Stori), a cross-sectional survey employing nationally-representative random sampling. Participants were 1,654 postpartum women within a year of giving birth. Chi-square test and logistic regression analysis were conducted to analyze the associations between social support (and other covariates) and postpartum depression. Among participants, 266 (16.1%) had postpartum depression. Depending on the level of social support, 6.0%, 53.9%, and 40.1% of them had low, moderate, and high social support, respectively. Women with moderate or low social support were more likely to have postpartum depression (OR = 1.78, 95% CI = 1.26-2.53; OR = 2.76, 95% CI = 1.56-4.89). This trend was observed in participants with multiparity, pregnancy loss, obese body image, and employed women. Social support was associated with a decreased likelihood of postpartum depression, indicating the importance of social support, especially for women experiencing multiparity, pregnancy loss, negative body image, as well as for employed women.

109Prevalence of depression and anxiety and correlations between depression, anxiety, family functioning, social support and coping styles among Chinese medical students.PubMed

Ruyue Shao, Ping He, Bin Ling, et al.
BMC Psychol. 2020 Apr 22;8(1):38. doi: 10.1186/s40359-020-00402-8.
BACKGROUND: Medical students experience depression and anxiety at a higher rate than the general population or students from other specialties. While there is a growing literature on the high prevalence of depression and anxiety symptoms and about potential risk factors to the prevalence of depression and anxiety symptoms among medical students, there is a paucity of evidence focused on the prevalence of depression and anxiety symptoms and associations with family function, social support and coping styles in Chinese vocational medicine students. This study aims to investigate the prevalence of depression and anxiety symptoms among Chinese medical students and assess the correlation between depression/anxiety symptoms and family function, social support and coping styles. METHODS: A sample of 2057 medical students from Chongqing Medical and Pharmaceutical College in China was investigated with a self-report questionnaire, which included demographic information, Zung self-rating depression scale, Zung Self-Rating Anxiety Scale, Family APGAR Index, Social Support Rating Scale and Trait Coping Style Questionnaire. RESULTS: The prevalence of depression and anxiety symptoms among the medical students was 57.5 and 30.8%, respectively. Older students(≥20 years) experienced higher levels of depression and anxiety. More depression and anxiety symptoms were exhibited among students with big financial burden, big study-induced stress and poor sleep quality. Students with large employment pressure showed more anxiety symptoms. Students who live alone or had bad relationship with their lovers or classmates or friends showed higher depression and anxiety scores. Depression and anxiety symptoms had highly significant correlations with family functioning, social support and coping style. CONCLUSIONS: Academic staffs should take measures to reduce depression and anxiety among medical students and to provide educational counseling and psychological support for students to cope with these problems.

110Social Support and Depression among Stroke Patients: A Topical Review.PubMed

Haoyu Zhou, Erin R Kulick
Int J Environ Res Public Health. 2023 Dec 8;20(24):7157. doi: 10.3390/ijerph20247157.
Research has shown a protective association between social support and depression, depression among stroke patients, and health impacts of depression. Despite this, not much is known about the effect of social support on depression among stroke patients. This review aims to summarize the current research examining the association between social support and depression among stroke patients. A literature search was performed in PubMed to find original peer-reviewed journal articles from 2016 to 12 March 2023 that examined the association between social support and depression among stroke patients. The search terms were depression and "social support" and stroke, which lead to 172 articles. After abstract review, seven observational studies that studied the target association among stroke patients were selected. One additional study was found using PsycINFO as a complementary source with the same search strategy and criteria. Overall, a negative association was found between social support and depression among stroke patients in eight studies, with more social support leading to lower rates of depression post-stroke. The other study did not find a statistically significant association. Overall, the results of recent studies suggest that social support is negatively associated with depression among stroke patients. In most studies, this association was statistically significant. The findings suggest the importance of improving social support perceived by stroke patients in the prevention of depression after the occurrence of stroke.

111Perceived social isolation makes me sad: 5-year cross-lagged analyses of loneliness and depressive symptomatology in the Chicago Health, Aging, and Social Relations Study.PubMed

John T Cacioppo, Louise C Hawkley, Ronald A Thisted
Psychol Aging. 2010 Jun;25(2):453-63. doi: 10.1037/a0017216.
We present evidence from a 5-year longitudinal study for the prospective associations between loneliness and depressive symptoms in a population-based, ethnically diverse sample of 229 men and women who were 50-68 years old at study onset. Cross-lagged panel models were used in which the criterion variables were loneliness and depressive symptoms, considered simultaneously. We used variations on this model to evaluate the possible effects of gender, ethnicity, education, physical functioning, medications, social network size, neuroticism, stressful life events, perceived stress, and social support on the observed associations between loneliness and depressive symptoms. Cross-lagged analyses indicated that loneliness predicted subsequent changes in depressive symptomatology, but not vice versa, and that this temporal association was not attributable to demographic variables, objective social isolation, dispositional negativity, stress, or social support. The importance of distinguishing between loneliness and depressive symptoms and the implications for loneliness and depressive symptomatology in older adults are discussed.

112Loneliness and depression in the elderly: the role of social network.PubMed

Joan Domènech-Abella, Elvira Lara, Maria Rubio-Valera, et al.
Soc Psychiatry Psychiatr Epidemiol. 2017 Apr;52(4):381-390. doi: 10.1007/s00127-017-1339-3. Epub 2017 Feb 2.
PURPOSE: Loneliness and depression are associated, in particular in older adults. Less is known about the role of social networks in this relationship. The present study analyzes the influence of social networks in the relationship between loneliness and depression in the older adult population in Spain. METHODS: A population-representative sample of 3535 adults aged 50 years and over from Spain was analyzed. Loneliness was assessed by means of the three-item UCLA Loneliness Scale. Social network characteristics were measured using the Berkman-Syme Social Network Index. Major depression in the previous 12 months was assessed with the Composite International Diagnostic Interview (CIDI). Logistic regression models were used to analyze the survey data. RESULTS: Feelings of loneliness were more prevalent in women, those who were younger (50-65), single, separated, divorced or widowed, living in a rural setting, with a lower frequency of social interactions and smaller social network, and with major depression. Among people feeling lonely, those with depression were more frequently married and had a small social network. Among those not feeling lonely, depression was associated with being previously married. In depressed people, feelings of loneliness were associated with having a small social network; while among those without depression, feelings of loneliness were associated with being married. CONCLUSION: The type and size of social networks have a role in the relationship between loneliness and depression. Increasing social interaction may be more beneficial than strategies based on improving maladaptive social cognition in loneliness to reduce the prevalence of depression among Spanish older adults.

113Social connectedness as a determinant of mental health: A scoping review.PubMed

Priya J Wickramaratne, Tenzin Yangchen, Lauren Lepow, et al.
PLoS One. 2022 Oct 13;17(10):e0275004. doi: 10.1371/journal.pone.0275004. eCollection 2022.
Public health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2021 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 66 unique studies. In research with other than pregnant women, 83% (19 of 23) studies reported that social support benefited symptoms of depression with the remaining 17% (5 of 23) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 83% (24 of 29 studies) found that low social support increased postpartum depressive symptoms. Among 8 of 9 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 8 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social connectedness protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.

114Polygenic risk of social isolation behavior and its influence on psychopathology and personality.PubMed

Adam J Socrates, Niamh Mullins, Ruben C Gur, et al.
Mol Psychiatry. 2024 Nov;29(11):3599-3606. doi: 10.1038/s41380-024-02617-2. Epub 2024 May 30.
Social isolation has been linked to a range of psychiatric issues, but the behavioral component that drives it is not well understood. Here, a genome-wide associations study (GWAS) was carried out to identify genetic variants that contribute specifically to social isolation behavior (SIB) in up to 449,609 participants from the UK Biobank. 17 loci were identified at genome-wide significance, contributing to a 4% SNP-based heritability estimate. Using the SIB GWAS, polygenic risk scores (PRS) were derived in ALSPAC, an independent, developmental cohort, and used to test for association with self-reported friendship scores, comprising items related to friendship quality and quantity, at age 12 and 18 to determine whether genetic predisposition manifests during childhood development. At age 18, friendship scores were associated with the SIB PRS, demonstrating that the genetic factors can predict related social traits in late adolescence. Linkage disequilibrium (LD) score correlation using the SIB GWAS demonstrated genetic correlations with autism spectrum disorder (ASD), schizophrenia, major depressive disorder (MDD), educational attainment, extraversion, and loneliness. However, no evidence of causality was found using a conservative Mendelian randomization approach between SIB and any of the traits in either direction. Genomic Structural Equation Modeling (SEM) revealed a common factor contributing to SIB, neuroticism, loneliness, MDD, and ASD, weakly correlated with a second common factor that contributes to psychiatric and psychotic traits. Our results show that SIB contributes a small heritable component, which is associated genetically with other social traits such as friendship as well as psychiatric disorders.

115Multiple risk factors predict recurrence of major depressive disorder in women.PubMed

Hanna M van Loo, Steven H Aggen, Charles O Gardner, et al.
J Affect Disord. 2015 Jul 15;180:52-61. doi: 10.1016/j.jad.2015.03.045. Epub 2015 Apr 2.
BACKGROUND: It is difficult to predict recurrence of depressive episodes in patients with major depression (MD): evidence for many risk factors is inconsistent and general prediction algorithms are lacking. The aim of this study was to develop a prediction model for recurrence of depressive episodes in women using improved methodology. METHODS: We used prospective data from a general population sample of female twins with a last-year MD episode (n=194). A rich set of baseline predictors was analyzed with Cox proportional hazards regression subject to elastic net regularization to find a model predicting recurrence of depressive episodes. Prediction accuracy of the model was assessed in an independent test sample (n=133), which was limited by the unavailability of a number of key predictors. RESULTS: A wide variety of risk factors predicted recurrence of depressive episodes in women: depressive and anxiety symptoms during the index episode, the level of symptoms at the moment of interview, psychiatric and family history, early and recent adverse life events, being unmarried, and problems with friends and finances. Kaplan Meier estimated survival curves showed that the model differentiated between patients at higher and lower risk for recurrence; estimated areas under the curve were in the range of 0.61-0.79. LIMITATIONS: Despite our rich set of predictors, certain potentially relevant variables were not available, such as biological measures, chronic somatic diseases, and treatment status. CONCLUSIONS: Recurrence of episodes of MD in women is highly multifactorial. Future studies should take this into account for the development of clinically useful prediction algorithms.

116Perinatal Depression: Challenges and Opportunities.PubMed

Rada K Dagher, Hannah E Bruckheim, Lisa J Colpe, et al.
J Womens Health (Larchmt). 2021 Feb;30(2):154-159. doi: 10.1089/jwh.2020.8862. Epub 2020 Nov 6.
Perinatal depression (PND) is a major depressive episode during pregnancy or within 4 weeks after childbirth up to a year. Risk factors for PND include stressful life events, history of depression, poor social support, unplanned and unwanted pregnancies, poor relationship quality, current or previous abuse, and low socioeconomic status. This mental disorder has been shown to have negative effects on mothers' quality of life and their intimate relationships, birth outcomes, and breastfeeding likelihood, as well as long-term effects on children's cognitive and emotional development. To date, no nationally representative study has examined whether there are socioeconomic and/or racial/ethnic differences in PND. This study discusses the prevalence and risk factors for PND, as well as its health consequences for mothers and children, the reasons for its underreporting and undertreatment, the evidence for different screening instruments and different treatment options, and the existing supportive policies to address this disorder in the United States. We conclude with outlining next steps in addressing the gaps in the literature on PND.

117Parenting styles, perceived social support and emotion regulation in adolescents with internet addiction.PubMed

Yusuf Karaer, Devrim Akdemir
Compr Psychiatry. 2019 Jul;92:22-27. doi: 10.1016/j.comppsych.2019.03.003. Epub 2019 Apr 3.
AIM: The aim of this study is to investigate parental attitudes, perceived social support, emotion regulation and the accompanying psychiatric disorders seen in adolescents who, having been diagnosed with Internet Addiction (IA), were referred to an outpatient child and adolescent psychiatric clinic. METHODS: Of 176 adolescents aged 12-17, 40 were included in the study group. These scored 80 or higher on Young's Internet Addiction Test (IAT) and met Young's diagnostic criteria for IA based on psychiatric interviews. Forty adolescents who matched them in terms of age, gender and socio-economic level were included in the control group. The Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL), the Parenting Style Scale (PSS), the Lum Emotional Availabilty of Parents (LEAP), the Social Support Appraisals Scale for Children (SSAS-C), the Difficulties in Emotion Regulation Scale (DERS) and the Toronto Alexithymia Scale-20 (TAS-20) were applied. RESULTS: The results showed that the parents of adolescents with IA were more frequently inadequate in acceptance/involvement, supervision/monitoring and they had less emotional availability. The adolescents with IA had less perceived social support, greater difficulty in the identification and verbal expression of their feelings and emotion regulation. Lower parental strictness/supervision, higher alexithymia and the existence of an anxiety disorder were found to be significant predictors of IA. Internet addicted adolescents with comorbid major depressive disorder had higher levels of alexithymia and lower levels of emotional availability in their parents. CONCLUSION: It can be concluded that strategies for the prevention and treatment of IA in adolescents should focus on improving the quality of parenting parent-adolescent relationships, enhancing perceived social support and emotion regulation while reducing the associated psychiatric symptoms in adolescents.

118Associations between loneliness and perceived social support and outcomes of mental health problems: a systematic review.PubMed

Jingyi Wang, Farhana Mann, Brynmor Lloyd-Evans, et al.
BMC Psychiatry. 2018 May 29;18(1):156. doi: 10.1186/s12888-018-1736-5.
BACKGROUND: The adverse effects of loneliness and of poor perceived social support on physical health and mortality are established, but no systematic synthesis is available of their relationship with the outcomes of mental health problems over time. In this systematic review, we aim to examine the evidence on whether loneliness and closely related concepts predict poor outcomes among adults with mental health problems. METHODS: We searched six databases and reference lists for longitudinal quantitative studies that examined the relationship between baseline measures of loneliness and poor perceived social support and outcomes at follow up. Thirty-four eligible papers were retrieved. Due to heterogeneity among included studies in clinical populations, predictor measures and outcomes, a narrative synthesis was conducted. RESULTS: We found substantial evidence from prospective studies that people with depression who perceive their social support as poorer have worse outcomes in terms of symptoms, recovery and social functioning. Loneliness has been investigated much less than perceived social support, but there is some evidence that greater loneliness predicts poorer depression outcome. There is also some preliminary evidence of associations between perceived social support and outcomes in schizophrenia, bipolar disorder and anxiety disorders. CONCLUSIONS: Loneliness and quality of social support in depression are potential targets for development and testing of interventions, while for other conditions further evidence is needed regarding relationships with outcomes.

119Maternal social support, quality of birth experience, and post-partum depression in primiparous women.PubMed

Franca Tani, Valeria Castagna
J Matern Fetal Neonatal Med. 2017 Mar;30(6):689-692. doi: 10.1080/14767058.2016.1182980. Epub 2016 May 20.
BACKGROUND: Social relationships provide individuals with a general sense of self-worth, psychological wellbeing, as well as allowing them access to resources during stressful periods and transitions in life. Pregnancy is a time of significant life change for every woman. The aim of this study was to verify the influence of social support perceived by mothers during pregnancy on the quality of their birth experience and post-partum depression. METHOD: A longitudinal study at three different times was carried out on 179 nulliparous pregnant women. Women completed a Maternal Social Support Questionnaire during the third trimester of their pregnancy. Then, on the first day after childbirth, clinical birth indices were collected. Finally, a month after childbirth, the Edinburgh Postnatal Depression Scale was administered. RESULTS: Post-partum depression was influenced negatively by maternal perceived social support and positively by negative clinical birth indices. In addition to these direct effects, analyses revealed a significant effect of maternal perceived social support on post-partum depression, mediated by the clinical indices considered. CONCLUSIONS: Social support perceived by mothers during pregnancy plays a significant role as a protection factor against post-partum depression, both directly and indirectly, reducing the negative clinical aspects of the birth experience.

120Association between postpartum depression level, social support level and breastfeeding attitude and breastfeeding self-efficacy in early postpartum women.PubMed

Yeliz Mercan, Kevser Tari Selcuk
PLoS One. 2021 Apr 2;16(4):e0249538. doi: 10.1371/journal.pone.0249538. eCollection 2021.
OBJECTIVE: The study was aimed at investigating the association between postpartum women's breastfeeding self-efficacy levels and their depression levels, social support levels, and breastfeeding attitudes in early postpartum period. METHODS: The cross-sectional study was carried out in Kirklareli in Turkey. The population of the study consisted of 398 women aged 15-49 in the first 42 days of the postpartum period who presented to eight family health centers. The study data were collected face-to-face using the Personal Information Form, Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF), Edinburgh Postnatal Depression Scale (EPDS), Multidimensional Scale of Perceived Social Support (MSPSS), and Breastfeeding Attitudes of the Evaluation Scale (BAES). RESULTS: The mean age of the participants was 28.61±5.72 (Min:18, Max: 44), and the mean score they obtained from the BSES-SF was 55.13±8.39. Statistically significant differences were detected between the participants' BSES-SF scores and age groups, employment status, perceived income level, and the number of living children (p < 0.05). No statistically significant differences were detected between marital status, educational status and BSES-SF scores (p > 0.05). In the multivariate regression analysis adjusted according to the sociodemographic characteristics, BAES, EPDS and MSPSS accounted for 48.3% of the BSES-SF. A negative association was found between BSES-SF scores and EPDS scores (β = -0.178, 95% CI:-0.349, -0.006), and a positive relation between the BAES scores (β = 0.194, 95% CI: 0.163, 0.226) and the MSPSS scores (β = 0.114, 95% CI: 0.037, 0.191). CONCLUSION: As the level of depression of women increases in the postpartum period, the level of breastfeeding self-efficacy decreases. The breastfeeding self-efficacy increases as the level of social support increases and as the attitudes that drive breastfeeding behavior change positively.

121Postpartum depression and social support: A longitudinal study of the first six months as parents.PubMed

Jie Zheng, Lingling Gao, Hanbing Li, et al.
J Clin Nurs. 2023 Jun;32(11-12):2652-2662. doi: 10.1111/jocn.16351. Epub 2022 May 10.
AIMS AND OBJECTIVES: The study aimed to (1) investigate the changes in maternal and paternal depression, along with social support, across the 6-month postpartum period; (2) explore the relationships between maternal and paternal depression and social support during the 6-month postpartum period; and (3) compare the differences in postpartum depression and social support between mothers and fathers at 2-3 days, 6 weeks, 3 months and 6 months postpartum. BACKGROUND: An increasing body of evidence now shows that postpartum depression affects both mothers and fathers. The notable increase in postpartum depression in China is particularly concerning. DESIGN: A longitudinal study was conducted, guided by the STROBE checklist. METHODS: 122 pairs of parents were recruited from September 2020 to October 2021 at a teaching hospital in Guangzhou, China. Data were collected from each parent at 2-3 days, 6 weeks, 3 months and 6 months postpartum, using the Edinburgh Postnatal Depression Scale and the Social Support Rating Scale. We also acquired socio-demographic and obstetric data at 2-3 days postpartum. RESULTS: Maternal depression was lowest at 2-3 days postpartum compared with that measured at 6 weeks, 3 months and 6 months postpartum. Maternal and paternal social support was highest at 2-3 days postpartum compared with that measured at 6 weeks, 3 months and 6 months postpartum. Maternal depression was significantly correlated with paternal depression while maternal social support was significantly correlated with paternal social support at different time points. CONCLUSION: Postpartum depression in mothers and social support in both mothers and fathers, showed significant changes during the 6-month postpartum period. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should pay attention to the mental health of both parents, view them as a team and provide both family-based and women-cantered interventions.

122Social support and depression among community dwelling older adults in Asia: a systematic review.PubMed

Tengku Amatullah Madeehah Tengku Mohd, Raudah Mohd Yunus, Farizah Hairi, et al.
BMJ Open. 2019 Jul 17;9(7):e026667. doi: 10.1136/bmjopen-2018-026667.
OBJECTIVES: This review aims to: (1) explore the social support measures in studies examining the association between social support and depression among community-dwelling older adults in Asia and (2) the evidence of association. DESIGN: A systematic review was conducted using electronic databases of CINAHL, PubMed, PsychINFO, Psychology and Behavioural Sciences Collection, SocINDEX and Web of Science for articles published until the 11th of January 2018. ELIGIBILITY CRITERIA: All observational studies investigating the association between social support and depression among community-dwelling older adults in Asia were included. PARTICIPANTS: Older adults aged 60 years and more who are living in the community. EXPOSURE MEASURES: Social support. OUTCOME MEASURES: Depression. RESULTS: We retrieved16 356 records and screened 66 full-text articles. Twenty-four observational studies were included in the review. They consisted of five cohort studies and 19 cross-sectional studies. Social support was found to be measured by multiple components, most commonly through a combination of structural and functional constructs. Perceived social support is more commonly measured compared with received social support. Good overall social support, having a spouse or partner, living with family, having a large social network, having more contact with family and friends, having emotional and instrumental support, good support from family and satisfaction with social support are associated with less depressive symptoms among community-dwelling older adults in Asia. CONCLUSIONS: There were 20 different social support measures and we applied a framework to allow for better comparability. Our findings emphasised the association between good social support and decrease depression among older adults. Compared with western populations, family support has a greater influence on depression among community-dwelling older adults in Asia. This indicates that the family institution needs to be incorporated into designed programmes and interventions when addressing depression in the Asian context. TRIAL : : CRD42017074897.

123Social support mediates social frailty with anxiety and depression.PubMed

Yang Liu, Mengjiao Yang, Yangyang Zhao, et al.
BMC Pulm Med. 2024 Aug 12;24(1):390. doi: 10.1186/s12890-024-03202-7.
BACKGROUND: Anxiety and depression are prevalent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, existing research has yielded conflicting findings regarding the effects of social frailty on anxiety and depression. The primary aim of this study is to validate the relationship between social frailty and social support with anxiety and depression in patients with acute exacerbations of COPD (AECOPD) and to investigate whether social support could explain the variations in prior study outcomes for patients with AECOPD. METHODS: Of the 315 patients hospitalized with AECOPD at the respiratory intensive care unit of a large tertiary care institution in Sichuan Province of China, between August 2022 and June 2023 who were surveyed, 306 were included in the analysis after excluding missing data. We conducted a logistic regression analysis to examine the associations of social frailty and social support with anxiety and depression and performed mediation analyses to examine whether social support mediates the relationship of social frailty with anxiety and depression. RESULTS: The logistic regression analysis revealed that social frailty did not associate anxiety or depression in patients with AECOPD. The mediation analysis supported this idea and indicated that while social frailty does not directly influence anxiety or depression, it can through social support. CONCLUSIONS: The findings suggest that while social frailty may not directly impact anxiety or depression in patients with AECOPD, social support plays a crucial mediating role. Enhancing social support can indirectly alleviate anxiety and depression among these patients. Enhancing social support networks should thus be prioritized by healthcare providers and family members to improve mental health outcomes in this patient population.

124EPA guidance on mental health and economic crises in Europe.PubMed

M Martin-Carrasco, S Evans-Lacko, G Dom, et al.
Eur Arch Psychiatry Clin Neurosci. 2016 Mar;266(2):89-124. doi: 10.1007/s00406-016-0681-x. Epub 2016 Feb 13.
This European Psychiatric Association (EPA) guidance paper is a result of the Working Group on Mental Health Consequences of Economic Crises of the EPA Council of National Psychiatric Associations. Its purpose is to identify the impact on mental health in Europe of the economic downturn and the measures that may be taken to respond to it. We performed a review of the existing literature that yields 350 articles on which our conclusions and recommendations are based. Evidence-based tables and recommendations were developed through an expert consensus process. Literature dealing with the consequences of economic turmoil on the health and health behaviours of the population is heterogeneous, and the results are not completely unequivocal. However, there is a broad consensus about the deleterious consequences of economic crises on mental health, particularly on psychological well-being, depression, anxiety disorders, insomnia, alcohol abuse, and suicidal behaviour. Unemployment, indebtedness, precarious working conditions, inequalities, lack of social connectedness, and housing instability emerge as main risk factors. Men at working age could be particularly at risk, together with previous low SES or stigmatized populations. Generalized austerity measures and poor developed welfare systems trend to increase the harmful effects of economic crises on mental health. Although many articles suggest limitations of existing research and provide suggestions for future research, there is relatively little discussion of policy approaches to address the negative impact of economic crises on mental health. The few studies that addressed policy questions suggested that the development of social protection programs such as active labour programs, social support systems, protection for housing instability, and better access to mental health care, particularly at primary care level, is strongly needed.

125Unemployment among young people and mental health: A systematic review.PubMed

Vicky H M Bartelink, Kyaw Zay Ya, Karin Guldbrandsson, et al.
Scand J Public Health. 2020 Jul;48(5):544-558. doi: 10.1177/1403494819852847. Epub 2019 Jul 10.
The aim of this systematic review is to obtain a better understanding of the association between unemployment among young people and mental health. : After screening the title and abstract of 794 articles drawn from four electronic databases, 52 articles remained for full-text reading. Of these, 20 studies met the inclusion criteria and were assessed on methodological quality. All steps were performed independently by two reviewers. Finally, a total of 17 articles were included in the systematic review. : Analysis of cross-sectional studies ( = 5) showed an association between unemployment among young people and mental health. An effect of unemployment on mental health was found when considering cohort studies ( = 12) that did not control for confounders (7/7). When controlling for confounders except mental health at baseline, this effect decreased in most studies leading to mixed results, although the majority (6/8) still found an effect. However, when taking mental health at baseline into account as one of the confounders, only a minority of studies (3/8) found a significant effect of unemployment on mental health.

126Economic crisis and mental health during the COVID-19 pandemic in Japan.PubMed

Tetsuya Matsubayashi, Yumi Ishikawa, Michiko Ueda
J Affect Disord. 2022 Jun 1;306:28-31. doi: 10.1016/j.jad.2022.03.037. Epub 2022 Mar 16.
BACKGROUND: The economic crisis induced by the COVID-19 pandemic can have a serious impact on population mental health. This study seeks to understand whether the economic shocks associated with the pandemic have a differential impact by sex because the current pandemic may have disproportionally affected women compared to men. METHODS: We analyzed data from original online monthly surveys of the general population in Japan conducted between April 2020 and February 2021 (N = 9000). We investigated whether individuals who had experienced a major job-related adverse change were more likely to have experienced depressive symptoms (PHQ-9) and anxiety disorders (GAD-7) during the pandemic and also if its effect varied by sex. RESULTS: The results of logistic regression suggest that depressive and anxiety symptoms were more prevalent among those who had recently experienced drastic changes in employment and working conditions, as well as among individuals with low income and those without college education. We also found that both female and male respondents who had experienced a major employment-related change exhibited depression and anxiety disorders. LIMITATIONS: We do not have data on the pre-COVID mental health conditions of our respondents, and our findings are descriptive. Some segments of the population may not be represented in our sample because our surveys were conducted online. CONCLUSIONS: COVID-induced economic shocks can have a detrimental effect on mental health among both economically vulnerable female and male workers.

127Health and unemployment.PubMed

D Dooley, J Fielding, L Levi
Annu Rev Public Health. 1996;17:449-65. doi: 10.1146/annurev.pu.17.050196.002313.
This paper reviews the relationship between health and inadequate employment, especially unemployment. Poor physical or mental health can lead, via poor work performance, to job loss; however, studies that control for such selection effects are still scarce except for a few health outcomes. For example, aggregate-level studies typically find a positive association between unemployment and suicide rates over time. At the individual level of analysis, panel surveys of laid-off workers tend to find increased psychiatric problems such as depression and substance abuse. Few studies have evaluated interventions to prevent or reduce the adverse health effects of job loss. There have been even fewer studies of the health effects of other types of inadequate employment such as the increasingly prevalent forms of underemployment.

128Mental health and unemployment: A systematic review and meta-analysis of interventions to improve depression and anxiety outcomes.PubMed

Andrew F Arena, Sophia Mobbs, Samineh Sanatkar, et al.
J Affect Disord. 2023 Aug 15;335:450-472. doi: 10.1016/j.jad.2023.05.027. Epub 2023 May 17.
BACKGROUND: Unemployment is associated with substantially greater depression and anxiety, constituting a considerable public health concern. The current review provides the most comprehensive synthesis to date, and first meta-analysis, of controlled intervention trials aimed at improving depression and anxiety outcomes during unemployment. METHODS: Searches were conducted within PsycInfo, Cochrane Central, PubMed and Embase from their inception to September 2022. Included studies conducted controlled trials of interventions focused on improving mental health within unemployed samples, and reported on validated measures of depression, anxiety, or distress (mixed depression and anxiety). Narrative syntheses and random effects meta-analyses were conducted among prevention- and treatment-level interventions for each outcome. RESULTS: A total of 39 articles reporting on 33 studies were included for review (sample sizes ranging from 21 to 1801). Both prevention and treatment interventions tended to be effective overall, with treatment interventions producing larger effect sizes than prevention interventions. The clearest evidence for particular intervention approaches emerged for prevention-level Cognitive Therapy/CBT, followed by prevention-level work-related interventions, although neither produced entirely consistent effects. LIMITATIONS: Risk of bias was generally high across studies. Low numbers of studies within subgroups precluded any comparisons between long-term and short-term unemployment, limited comparisons among treatment studies, and reduced the power of meta-analyses. CONCLUSIONS: Both prevention- and treatment-level mental health-focused interventions have merit for reducing symptoms of anxiety and depression among those experiencing unemployment. Cognitive Therapy/CBT and work-related interventions hold the most robust evidence base, which can inform both prevention and treatment strategies implemented by clinicians, employment services providers, and governments.

129Social determinants of health and depression: a preliminary investigation from rural China.PubMed

Yuan Liang, Yan-Hong Gong, Xiao-Piao Wen, et al.
PLoS One. 2012;7(1):e30553. doi: 10.1371/journal.pone.0030553. Epub 2012 Jan 19.
BACKGROUND: In the last several years, research related to social determinants of health (SDH) has begun to resonate in the medical, behavioral, social and political sciences arena. The aim of the present study was to explore the relationship between SDH and depression, and to provide new evidences and clues for depression control and prevention. METHODOLOGY/PRINCIPAL FINDINGS: This research was a cross-sectional survey executed door to door from October 2006 to April 2008, with a sample of 3,738 individuals aged 18 and older in rural China. The three variables of SDH were socioeconomic status (years of schooling and self-reported economic status of family), social cohesion and negative life events. Demographic variables and self-perceived physical health were taken as potential confounders. The cross-table analysis showed that variations in levels of depression were associated with variations in SDH, and logistic regression analysis confirmed the association even after adjusting for potential confounding variables. CONCLUSIONS: Although there were some limitations, the current study provides initial evidence of the importance of SDH in depression. Findings indicate that social inequity and the role of policy action emphasized by SDH should be considered high priorities when addressing the issue of depression. In addition, cell-to-society and pill-to-policy approaches should be encouraged in the future.

130Ten Surprising Facts About Stressful Life Events and Disease Risk.PubMed

Sheldon Cohen, Michael L M Murphy, Aric A Prather
Annu Rev Psychol. 2019 Jan 4;70:577-597. doi: 10.1146/annurev-psych-010418-102857. Epub 2018 Jun 27.
After over 70 years of research on the association between stressful life events and health, it is generally accepted that we have a good understanding of the role of stressors in disease risk. In this review, we highlight that knowledge but also emphasize misunderstandings and weaknesses in this literature with the hope of triggering further theoretical and empirical development. We organize this review in a somewhat provocative manner, with each section focusing on an important issue in the literature where we feel that there has been some misunderstanding of the evidence and its implications. Issues that we address include the definition of a stressful event, characteristics of diseases that are impacted by events, differences in the effects of chronic and acute events, the cumulative effects of events, differences in events across the life course, differences in events for men and women, resilience to events, and methodological challenges in the literature.

131Social determinants of health and gender differences in depression among adults: A cohort study.PubMed

Feixiang Zhou, Simin He, Jingliang Shuai, et al.
Psychiatry Res. 2023 Nov;329:115548. doi: 10.1016/j.psychres.2023.115548. Epub 2023 Oct 16.
The role of social determinants of health (SDoH) in gender differences in depression remains unclear among Chinese adults. We aimed to explore the association between SDoH and depression and investigate their role in explaining gender differences in depression. This prospective longitudinal cohort study used four wave surveys (2012, 2016, 2018, and 2020) of the China Family Panel Study (CFPS). Fourteen SDoH variables were assessed, and depression was measured using the 8-item short version of the Center for Epidemiologic Studies Depression Scale. The Cox proportional hazards regression and multiple mediation analysis were performed to estimate the effect sizes. The longitudinal sample included 18,874 participants aged 18-92 years (51.4 % males and 48.6 % females). Women had higher risk of depression than men. Unfavorable SDoH were associated with higher risk of depression. After including multiple SDoH in mediation analysis, multiple SDoH mediated 15.7 % of the total effect of gender on depression. In sum, SDoH significantly influenced depression, and specific factors explained gender differences in depression. Supporting women in education, employment, and community involvement could help reduce gender differences in depression.

132Non-motor features of Parkinson disease.PubMed

Anthony H V Schapira, K Ray Chaudhuri, Peter Jenner
Nat Rev Neurosci. 2017 Jul;18(7):435-450. doi: 10.1038/nrn.2017.62. Epub 2017 Jun 8.
Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.

133Post-stroke depression: A 2020 updated review.PubMed

Gustavo C Medeiros, Durga Roy, Nicholas Kontos, et al.
Gen Hosp Psychiatry. 2020 Sep-Oct;66:70-80. doi: 10.1016/j.genhosppsych.2020.06.011. Epub 2020 Jun 27.
BACKGROUND: Post-stroke depression (PSD) is common and associated with higher mortality, poorer recovery, more pronounced cognitive deficits, and lower quality of life than is stroke without depression. This manuscript will conduct an updated, comprehensive and clinically-useful review of the risk factors, pathophysiology, assessment, prevention, and treatment of PSD. METHODS: This narrative review summarizes articles obtained on PubMed, Medline, EMBase, Google Scholar and the Cochrane Database. This review prioritized articles with a more robust level of evidence, such as original articles with longitudinal data and/or larger samples, randomized controlled trials, systematic reviews, and metaanalyses. RESULTS: One hundred twenty-four articles were reviewed, of which 44 (35%) were published before 2016 and 80 (65%) that were published since 2016. DISCUSSION: Rates of PSD range from 18 to 33%, yet it is vastly underdiagnosed and undertreated. Risk factors for PSD include female sex, history of psychiatric illness, large or multiple strokes, injuries in frontal/anterior areas or in the basal ganglia, stroke occurrence within the past year, poor social support, and pronounced disability. The pathophysiology of PSD is multifactorial and likely involves decreased levels of monoamines, abnormal neurotrophic response, increased inflammation with dysregulation of hypothalamic-pituitary-adrenal axis, and glutamate-mediated excitotoxicity. The evidence for preventive interventions for PSD is somewhat inconsistent and modest. The best treatment for PSD consists of the combination of pharmacological, psychosocial and stroke-focused interventions. CONCLUSION: PSD is a common, treatable condition that is associated with several negative outcomes. Early detection and proper management are critical to obtain better outcomes in individuals with PSD.

134Post-Stroke Depression: A Review.PubMed

Robert G Robinson, Ricardo E Jorge
Am J Psychiatry. 2016 Mar 1;173(3):221-31. doi: 10.1176/appi.ajp.2015.15030363. Epub 2015 Dec 18.
Poststroke depression (PSD) has been recognized by psychiatrists for more than 100 years, but controlled systematic studies did not begin until the 1970s. Meta-analyses addressing almost all major clinical issues in the field have emerged because of the relatively small number of patients included in some stroke studies. In order to build large databases, these meta-analyses have merged patients with rigorously assessed mood disorders with major depressive features with patients scoring above arbitrary cutoff points on depression rating scales, thus missing important findings such as cognitive impairment associated with major but not minor depression. Nevertheless, PSD occurs in a significant number of patients and constitutes an important complication of stroke, leading to greater disability as well as increased mortality. The most clinically important advances, however, have been in the treatment and prevention of PSD. Recent meta-analyses of randomized controlled trials for the treatment of PSD have demonstrated the efficacy of antidepressants. Similarly, randomized controlled trials for prevention of PSD have shown that antidepressants significantly decrease the incidence of PSD compared with placebo. Early antidepressant treatment of PSD appears to enhance both physical and cognitive recovery from stroke and might increase survival up to 10 years following stroke. There has also been progress in understanding the pathophysiology of PSD. Inflammatory processes might be associated with the onset of at least some depressive symptoms. In addition, genetic and epigenetic variations, white matter disease, cerebrovascular deregulation, altered neuroplasticity, and changes in glutamate neurotransmission might be relevant etiological factors. Further elucidation of the mechanism of PSD may ultimately lead to specific targeted treatments.

135Pathophysiology and Current Drug Treatments for Post-Stroke Depression: A Review.PubMed

Dmitry Frank, Benjamin F Gruenbaum, Alexander Zlotnik, et al.
Int J Mol Sci. 2022 Dec 1;23(23):15114. doi: 10.3390/ijms232315114.
Post-stroke depression (PSD) is a biopsychosocial disorder that affects individuals who have suffered a stroke at any point. PSD has a 20 to 60 percent reported prevalence among stroke survivors. Its effects are usually adverse, can lead to disability, and may increase mortality if not managed or treated early. PSD is linked to several other medical conditions, including anxiety, hyper-locomotor activity, and poor functional recovery. Despite significant awareness of its adverse impacts, understanding the pathogenesis of PSD has proved challenging. The exact pathophysiology of PSD is unknown, yet its complexity has been definitively shown, involving mechanisms such as dysfunction of monoamine, the glutamatergic systems, the gut-brain axis, and neuroinflammation. The current effectiveness of PSD treatment is about 30-40 percent of all cases. In this review, we examined different pathophysiological mechanisms and current pharmacological and non-pharmacological approaches for the treatment of PSD.

136Chronic Pain and Mental Health Disorders: Shared Neural Mechanisms, Epidemiology, and Treatment.PubMed

W Michael Hooten
Mayo Clin Proc. 2016 Jul;91(7):955-70. doi: 10.1016/j.mayocp.2016.04.029. Epub 2016 Jun 22.
Chronic pain and mental health disorders are common in the general population, and epidemiological studies suggest that a bidirectional relationship exists between these 2 conditions. The observations from functional imaging studies suggest that this bidirectional relationship is due in part to shared neural mechanisms. In addition to depression, anxiety, and substance use disorders, individuals with chronic pain are at risk of other mental health problems including suicide and cigarette smoking and many have sustained sexual violence. Within the broader biopsychosocial model of pain, the fear-avoidance model explains how behavioral factors affect the temporal course of chronic pain and provides the framework for an array of efficacious behavioral interventions including cognitive-behavioral therapy, acceptance-based therapies, and multidisciplinary pain rehabilitation. Concomitant pain and mental health disorders often complicate pharmacological management, but several drug classes, including serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and anticonvulsants, have efficacy for both conditions and should be considered first-line treatment agents.

137Bidirectional relationship between chronic pain and depressive symptoms in middle-aged and older adults.PubMed

André O Werneck, Brendon Stubbs
Gen Hosp Psychiatry. 2024 Jul-Aug;89:49-54. doi: 10.1016/j.genhosppsych.2024.05.007. Epub 2024 May 11.
OBJECTIVE: To assess the bidirectional association between chronic pain and depressive symptoms among middle-aged and older adults from two prospective cohort studies. METHODS: We used prospective data (12y of follow-up) from the English Longitudinal Study of Ageing (n = 9149, 5018 women, 65.0 ± 10.2y) and the Health and Retirement Study (n = 16,883, 9810 women, 66.9 ± 10.3y), including data from seven waves of each cohort between 2006 and 2018/2019. Depressive symptoms were assessed using the Centre of Epidemiological Studies Depression scale, while chronic pain was estimated using questions about the frequency of being troubled with pain. We used random-intercept cross-lagged panel models to assess the bidirectional association between pain and depressive symptoms, adjusting for potential confounders. RESULTS: There was a cross-lagged effect of chronic pain on depressive symptoms (ELSA: β: 0.038; 95%CI: 0.011-0.066. Standardized coefficient (B): 0.021. SHARE: β: 0.044; 95%CI: 0.023-0.065. B: 0.023-0.024) as well as depressive symptoms on pain (ELSA: β: 0.010; 95%CI: 0.002-0.018. B: 0.017-0.019. SHARE: 0.011; 95%CI: 0.005-0.017. B: 0.020-0.021). Moreover, there were auto-regressive effects of both chronic pain (ELSA: β: 0.149; 95%CI: 0.128-0.171. SHARE: β: 0.129; 95%CI: 0.112-0.145) and depressive symptoms (ELSA: β: 0.149; 95%CI: 0.130-0.168. SHARE: β: 0.169; 95%CI: 0.154-0.184). CONCLUSION: We identified a modest bidirectional association between depressive symptoms and chronic pain, using two large prospective ageing cohorts.

138The Role of Kynurenine and Its Metabolites in Comorbid Chronic Pain and Depression.PubMed

Onella Athnaiel, Charmaine Ong, Nebojsa Nick Knezevic
Metabolites. 2022 Oct 6;12(10):950. doi: 10.3390/metabo12100950.
Chronic pain and depression affect millions of people worldwide, and their comorbidity tends to exacerbate the severity of each individual condition. Intersecting brain regions and molecular pathways could probably explain the unique yet complex bidirectional relationship between these two disorders. Recent studies have found that inflammatory reactions, frequently identified in both chronic pain and depression, stimulate certain enzymes in the kynurenine pathway, while concurrently suppressing others. Kynurenine, a major tryptophan derivative, and its metabolites have been implicated in several inflammation-associated pain syndromes and depressive mood disorders. Due to inflammation, 95% of tryptophan is metabolized via the kynurenine pathway, which drives the reaction towards the production of metabolites that have distinct roles in the pathophysiology of these disorders. Diminished levels of the neuroprotective metabolite, kynurenic acid (KYNA), and elevated levels of the neurotoxic metabolite, quinolinic acid (QUIN), have been frequently identified in human patients formally diagnosed with these disorders, as well as animal models commonly used in medical research. This review not only explores the epidemiology of comorbid chronic pain and depression, but also highlights the involvement of kynurenine and its metabolites, specifically KYNA and QUIN, in these pervasive conditions.

139Depression and coronary heart disease.PubMed

Robert M Carney, Kenneth E Freedland
Nat Rev Cardiol. 2017 Mar;14(3):145-155. doi: 10.1038/nrcardio.2016.181. Epub 2016 Nov 17.
Depression is a highly prevalent risk factor for incident coronary heart disease (CHD) and for cardiovascular morbidity and mortality in patients with established CHD. Several biological and behavioural mechanisms have been hypothesized to underlie the relationship between depression and CHD, but none has been shown to account for more than a small proportion of the risk. Only a few clinical trials have examined whether treating depression decreases the risk of cardiac events in patients with established CHD. None of these trials has shown that treatment results in improved cardiac outcomes, but the differences in depression outcomes between the intervention and control groups have been small and not clinically significant. Nevertheless, secondary analyses of these trials suggest that prognosis improves when depression improves. Concerted efforts to develop more potent interventions for depression, identification of high-risk subtypes of depression, and further research on the biobehavioural mechanisms linking depression to CHD are needed to pave the way for definitive clinical trials.

140Depression and obesity: evidence of shared biological mechanisms.PubMed

Yuri Milaneschi, W Kyle Simmons, Elisabeth F C van Rossum, et al.
Mol Psychiatry. 2019 Jan;24(1):18-33. doi: 10.1038/s41380-018-0017-5. Epub 2018 Feb 16.
Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.

141Depression severity as a predictor of cardiovascular-kidney-metabolic syndrome progression and mortality: Results from two nationally representative cohort studies.PubMed

Yujian He, Lijuan Lan, Yuting Liu, et al.
J Affect Disord. 2025 Nov 1;388:119606. doi: 10.1016/j.jad.2025.119606. Epub 2025 Jun 4.
BACKGROUND: Depression is a common mental disorder linked to adverse clinical outcomes; however, its impact on the progression and prognosis of cardiovascular-kidney-metabolic (CKM) syndrome remains unclear. This study aimed to investigate whether higher depression severity is associated with an increased risk of CKM progression and to evaluate its prognostic significance for all-cause mortality. METHODS: We analyzed data from two large, nationally representative cohorts: the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS). Multivariable logistic regression and Cox proportional hazards models were employed to examine the associations between depression scores, CKM progression and mortality. Restricted cubic spline and Receiver operating characteristic analyses explored nonlinear relationships and predictive performance. RESULTS: A total of 8571 NHANES participants and 7635 CHARLS participants were included in this study. Each 1-point increase in depression score correlated with a 7 % elevated risk of advanced CKM stage in both cohorts (adjusted OR = 1.07, 95 % CI: 1.06-1.09 for NHANES; OR = 1.07, 1.05-1.08 for CHARLS). Severe depression conferred the highest risk (NHANES: OR = 3.58, 2.04-6.30; CHARLS: OR = 3.06, 2.38-3.93). Depression scores predicted mortality, with HRs of 1.04 (1.02-1.05) per PHQ-9 point and 1.02 (1.00-1.03) per CES-D-10 point. Nonlinear (NHANES) and linear (CHARLS) trends were observed in RCS analyses. ROC curves demonstrated moderate predictive accuracy (AUC: 0.615 for CES-D-10; 0.580 for PHQ-9). CONCLUSION: Higher depression severity is independently associated with CKM progression and increased mortality risk, underscoring its clinical utility for risk stratification. Integration of depression screening into CKM management may enhance early intervention and improve outcomes.

142Depression in cancer: The many biobehavioral pathways driving tumor progression.PubMed

Beatrice Bortolato, Thomas N Hyphantis, Sara Valpione, et al.
Cancer Treat Rev. 2017 Jan;52:58-70. doi: 10.1016/j.ctrv.2016.11.004. Epub 2016 Nov 16.
Major Depressive Disorder (MDD) is common among cancer patients, with prevalence rates up to four-times higher than the general population. Depression confers worse outcomes, including non-adherence to treatment and increased mortality in the oncology setting. Advances in the understanding of neurobiological underpinnings of depression have revealed shared biobehavioral mechanisms may contribute to cancer progression. Moreover, psychosocial stressors in cancer promote: (1) inflammation and oxidative/nitrosative stress; (2) a decreased immunosurveillance; and (3) a dysfunctional activation of the autonomic nervous system and of the hypothalamic-pituitaryadrenal axis. Consequently, the prompt recognition of depression among patients with cancer who may benefit of treatment strategies targeting depressive symptoms, cognitive dysfunction, fatigue and sleep disturbances, is a public health priority. Moreover, behavioral strategies aiming at reducing psychological distress and depressive symptoms, including addressing unhealthy diet and life-style choices, as well as physical inactivity and sleep dysfunction, may represent important strategies not only to treat depression, but also to improve wider cancer-related outcomes. Herein, we provide a comprehensive review of the intertwined biobehavioral pathways linking depression to cancer progression. In addition, the clinical implications of these findings are critically reviewed.

143The Role of Early Life Stress in HPA Axis and Anxiety.PubMed

Mario F Juruena, Filip Eror, Anthony J Cleare, et al.
Adv Exp Med Biol. 2020;1191:141-153. doi: 10.1007/978-981-32-9705-0_9.
Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of psychiatric syndromes, particularly affective disorders, including anxiety disorders, and is therefore a significant health problem.This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and generalized anxiety disorder (GAD), panic disorder, and phobias and the role of early life stress as an important risk factor for HPA axis dysfunction.The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including panic, GAD, phobias and anxiety. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the anxiety syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysfunction of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in anxiety disorders. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. Early stressful life events may provoke alterations of the stress response and thus of the HPA axis that can endure during adulthood, predisposing individuals to develop psychopathology.

144The HPA axis dysregulation in severe mental illness: Can we shift the blame to gut microbiota?PubMed

Błażej Misiak, Igor Łoniewski, Wojciech Marlicz, et al.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Aug 30;102:109951. doi: 10.1016/j.pnpbp.2020.109951. Epub 2020 Apr 23.
Accumulating evidence indicates that patients with severe mental disorders, including major depression, bipolar disorder and schizophrenia present with various alterations of the gut microbiota and increased intestinal permeability. In addition, the hypothalamic-pituitary-adrenal (HPA) axis dysregulation and subclinical inflammation have been reported in this group of patients. Although it has been found that the HPA axis dysregulation appears as a consequence of psychosocial stress, especially traumatic life events, the exact mechanisms of this observation remain unclear. Animal model studies have unraveled several mechanisms linking the gut microbiota with the HPA axis dysfunction. Indeed, the gut microbiota can activate the HPA axis through several mediators that cross the blood-brain barrier and include microbial antigens, cytokines and prostaglandins. There is also evidence that various microbial species can affect ileal corticosterone production that may impact the activity of the HPA axis. However, some metabolites released by various microbes, e.g., short-chain fatty acids, can attenuate the HPA axis response. Moreover, several bacteria release neurotransmitters that can directly interact with vagal afferents. It has been postulated that the HPA axis activation can impact the gut microbiota and intestinal permeability. In this article, we discuss various mechanisms linking the gut microbiota with the HPA axis activity and summarize current evidence for a cross-talk between the gut-brain axis and the HPA axis from studies of patients with mood and psychotic disorders. Finally, we show potential clinical implications that can arise from future studies investigating the HPA axis activity with respect to the gut microbiota in severe mental disorders.

145Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.PubMed

Wei-Zhu Liu, Wen-Hua Zhang, Zhi-Heng Zheng, et al.
Nat Commun. 2020 May 6;11(1):2221. doi: 10.1038/s41467-020-15920-7.
Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders. Here we show that, in a rodent anxiety model induced by chronic restraint stress (CRS), the dysregulation occurs in basolateral amygdala projection neurons receiving mono-directional inputs from dorsomedial prefrontal cortex (dmPFC→BLA PNs) rather than those reciprocally connected with dmPFC (dmPFC↔BLA PNs). Specifically, CRS shifts the dmPFC-driven excitatory-inhibitory balance towards excitation in the former, but not latter population. Such specificity is preferential to connections made by dmPFC, caused by enhanced presynaptic glutamate release, and highly correlated with the increased anxiety-like behavior in stressed mice. Importantly, low-frequency optogenetic stimulation of dmPFC afferents in BLA normalizes the enhanced prefrontal glutamate release onto dmPFC→BLA PNs and lastingly attenuates CRS-induced increase of anxiety-like behavior. Our findings thus reveal a target cell-based dysregulation of mPFC-to-amygdala transmission for stress-induced anxiety.

146Antidepressants in the treatment of bipolar depression: commentary.PubMed

Gustavo H Vázquez, Ross J Baldessarini
Int J Neuropsychopharmacol. 2025 Mar 20;28(3). doi: 10.1093/ijnp/pyaf013.
BACKGROUND: Depression is a therapeutic challenge with bipolar disorder (BD) patients and remains a major contributor to disability, comorbidity, and premature mortality. The efficacy and safety of antidepressants (ADs) for this indication remain particularly controversial, and optimally safe and effective treatment of bipolar (BP) depression remains uncertain. METHOD: We summarized selected research findings on the treatment of depression in BD aimed at supporting practical guidelines for clinical treatment involving ADs. RESULTS: Growing research evidence indicates that ADs are probably effective in BP depression and possibly not less than in major depressive disorder. Tolerability of antidepressant (AD) treatment is greater with type II BD (BD-2) than with type I (BD-1), particularly when ADs are combined with a mood stabilizer or antipsychotic. For BP depression, preferred ADs are serotonin-reuptake inhibitors and bupropion given in moderate doses for limited times. CONCLUSIONS: Optimal treatment of depression requires further investigation, particularly for long-term maintenance. Nevertheless, treatment for acute depressive episodes can usefully and safely include some ADs in moderate doses for limited duration, best combined with lithium, some anticonvulsants, or certain atypical antipsychotics, and more safely with BD-2 than BD-1 with close clinical supervision.

147Mifepristone as a therapeutic agent in psychiatry.PubMed

Robert H Howland
J Psychosoc Nurs Ment Health Serv. 2013 Jun;51(6):11-4. doi: 10.3928/02793695-20130513-01.
The hypothalamic-pituitary-adrenal (HPA) axis is the body's main stress-response system, and cortisol is the major adrenal glucocorticoid hormone secreted in human beings. HPA axis activity and cortisol secretion is regulated by a negative feedback system involving glucocorticoid receptors. Dysregulation of the HPA axis and increased cortisol levels have been implicated in mood, psychotic, and other psychiatric disorders. Mifepristone, as a potent antagonist of glucocorticoid receptors, has been studied or is currently being investigated as a potential therapeutic agent for psychotic depression, posttraumatic stress disorder, and alcohol and cocaine dependence, as well as for mitigating the weight gain associated with the use of antipsychotic drugs and for improving cognitive dysfunction in schizophrenia and bipolar disorder. This article will review some of the work in these areas.

148Depression and borderline personality disorder.PubMed

Josephine A Beatson, Sathya Rao
Med J Aust. 2013 Sep 16;199(6 Suppl):S24-7. doi: 10.5694/mja12.10474.
Borderline personality disorder (BPD) is a serious mental illness characterised by dysregulation of emotions and impulses, an unstable sense of self, and difficulties in interpersonal relationships, often accompanied by suicidal and self-harming behaviour. Major depressive disorder (MDD) commonly co-occurs with BPD. Patients with BPD often present with depressive symptoms. It can be difficult to distinguish between BPD and MDD, especially when the two disorders co-occur. Research is needed to clarify the commonalities and differences between BPD and MDD, and BPD and rapid-cycling bipolar disorder. When MDD and BPD co-occur, both conditions should be treated concurrently. MDD co-occurring with BPD does not respond as well to antidepressant medication as MDD in the absence of BPD. MDD is not a significant predictor of outcome for BPD, but BPD is a significant predictor of outcome for MDD. Treatment of BPD with specific psychotherapies tends to result in remission of co-occurring MDD. Empirically validated psychotherapies for BPD share common features that are applicable in all treatment settings where patients with BPD are likely to present, including primary care. Methodologically sound research is required to examine the effectiveness of medications for treatment of MDD co-occurring with BPD.

149Prevalence and incidence of postpartum depression among healthy mothers: A systematic review and meta-analysis.PubMed

Shefaly Shorey, Cornelia Yin Ing Chee, Esperanza Debby Ng, et al.
J Psychiatr Res. 2018 Sep;104:235-248. doi: 10.1016/j.jpsychires.2018.08.001. Epub 2018 Aug 3.
This review aims to examine the prevalence and incidence of postpartum depression among healthy mothers without prior history of depression including postpartum depression and who gave birth to healthy full-term infants. A systematic search of ClinicalTrials.gov, CINAHL, EMBASE, PsycINFO, and PubMed was performed for English articles from the inception of the database to November 2017, as well as a manual search of the reference lists of the included articles, and an expert panel was consulted. Across 15,895 articles, 58 articles (N = 37,294 women) were included in the review. The incidence of postpartum depression was 12% [95% CI 0.04-0.20] while the overall prevalence of depression was 17% [95% CI 0.15-0.20] among healthy mothers without a prior history of depression. Prevalence was similar regardless of the type of diagnostic tool used; however, there were statistical differences in the prevalence between different geographical regions, with the Middle-East having the highest prevalence (26%, 95% CI 0.13-0.39) and Europe having the lowest (8%, 95% CI 0.05-0.11). There was no statistical difference in prevalence between different screening time points, but an increasing prevalence was observed beyond six months postpartum. Intervention studies often neglect healthy mothers. This review reports a similar prevalence rate of postpartum depression among mothers without history of depression when compared to mothers with history of depression. Thus, future studies should place equal emphasis on this neglected group of mothers so that targeted interventions and follow-ups can be introduced at appropriate time points.

150Perinatal depression: a systematic review of prevalence and incidence.PubMed

Norma I Gavin, Bradley N Gaynes, Kathleen N Lohr, et al.
Obstet Gynecol. 2005 Nov;106(5 Pt 1):1071-83. doi: 10.1097/01.AOG.0000183597.31630.db.
OBJECTIVE: We systematically review evidence on the prevalence and incidence of perinatal depression and compare these rates with those of depression in women at non-childbearing times. DATA SOURCES: We searched MEDLINE, CINAHL, PsycINFO, and Sociofile for English-language articles published from 1980 through March 2004, conducted hand searches of bibliographies, and consulted with experts. METHODS OF STUDY SELECTION: We included cross-sectional, cohort, and case-control studies from developed countries that assessed women for depression during pregnancy or the first year postpartum with a structured clinical interview. TABULATION, INTEGRATION, AND RESULTS: Of the 109 articles reviewed, 28 met our inclusion criteria. For major and minor depression (major depression alone), the combined point prevalence estimates from meta-analyses ranged from 6.5% to 12.9% (1.0-5.6%) at different trimesters of pregnancy and months in the first postpartum year. The combined period prevalence shows that as many as 19.2% (7.1%) of women have a depressive episode (major depressive episode) during the first 3 months postpartum; most of these episodes have onset following delivery. All estimates have wide 95% confidence intervals, showing significant uncertainty in their true levels. No conclusions could be made regarding the relative incidence of depression among pregnant and postpartum women compared with women at non-childbearing times. CONCLUSION: To better delineate periods of peak prevalence and incidence for perinatal depression and identify high risk subpopulations, we need studies with larger and more representative samples.

151Screening of Perinatal Depression Using the Edinburgh Postpartum Depression Scale.PubMed

Tenilson Amaral Oliveira, Guilherme Guarany Cardoso Magalhães Luzetti, Márcia Maria Auxiliadora Rosalém, et al.
Rev Bras Ginecol Obstet. 2022 May;44(5):452-457. doi: 10.1055/s-0042-1743095. Epub 2022 Mar 4.
OBJECTIVE: To detect depression during pregnancy and in the immediate postpartum period using the Edinburgh postpartum depression scale (EPDS). METHODS: Cross sectional study of 315 women, aged between 14 and 44 years, who received perinatal care at the Leonor Mendes de Barros Hospital, in São Paulo, between July 1st, 2019 and October 30th, 2020. The cutoff point suggesting depression was ≥ 12. RESULTS: The screening indicated 62 (19.7%) patients experiencing depression. Low family income, multiparity, fewer prenatal appointments, antecedents of emotional disorders, dissatisfaction with the pregnancy, poor relationship with the partner, and psychological aggression were all risk factors associated with depression in pregnancy or in the immediate postpartum period. Antecedents of depression and psychology aggression during pregnancy were significant variables for predicting perinatal depression in the multivariate analysis. CONCLUSION: There is a significant association between the occurrence of perinatal depression and the aforementioned psychosocial factors. Screening patients with the EPDS during perinatal and postpartum care could facilitate establishing a line of care to improve the wellbeing of mother and infant.

152The role of reproductive hormones in postpartum depression.PubMed

Crystal Edler Schiller, Samantha Meltzer-Brody, David R Rubinow
CNS Spectr. 2015 Feb;20(1):48-59. doi: 10.1017/S1092852914000480. Epub 2014 Sep 29.
Despite decades of research aimed at identifying the causes of postpartum depression (PPD), PPD remains common, and the causes are poorly understood. Many have attributed the onset of PPD to the rapid perinatal change in reproductive hormones. Although a number of human and nonhuman animal studies support the role of reproductive hormones in PPD, several studies have failed to detect an association between hormone concentrations and PPD. The purpose of this review is to examine the hypothesis that fluctuations in reproductive hormone levels during pregnancy and the postpartum period trigger PPD in susceptible women. We discuss and integrate the literature on animal models of PPD and human studies of reproductive hormones and PPD. We also discuss alternative biological models of PPD to demonstrate the potential for multiple PPD phenotypes and to describe the complex interplay of changing reproductive hormones and alterations in thyroid function, immune function, hypothalamic-pituitary-adrenal (HPA) axis function, lactogenic hormones, and genetic expression that may contribute to affective dysfunction. There are 3 primary lines of inquiry that have addressed the role of reproductive hormones in PPD: nonhuman animal studies, correlational studies of postpartum hormone levels and mood symptoms, and hormone manipulation studies. Reproductive hormones influence virtually every biological system implicated in PPD, and a subgroup of women seem to be particularly sensitive to the effects of perinatal changes in hormone levels. We propose that these women constitute a "hormone-sensitive" PPD phenotype, which should be studied independent of other PPD phenotypes to identify underlying pathophysiology and develop novel treatment targets.

153Oestrogens and progestins for preventing and treating postpartum depression.PubMed

Cindy-Lee Dennis, Lori E Ross, Andrew Herxheimer
Cochrane Database Syst Rev. 2008 Oct 8;2008(4):CD001690. doi: 10.1002/14651858.CD001690.pub2.
BACKGROUND: Postpartum depression is a common complication of childbirth, affecting approximately 13% of women. A hormonal aetiology has long been hypothesised due to the sudden and substantial fluctuations in concentrations of steroid hormones associated with pregnancy and the immediate postpartum period. There is also convincing evidence that oestrogens, progestins, and related compounds have important central nervous system activity at physiological concentrations. OBJECTIVES: The primary objective of this review was to assess the effects of oestrogens and progestins, including natural progesterone and synthetic progestogens, compared with placebo or usual antepartum, intrapartum, or postpartum care in the prevention and treatment of postpartum depression. SEARCH STRATEGY: We searched The Cochrane Pregnancy and Childbirth Group trials register (June 2004), the Cochrane Depression Anxiety and Neurosis Group trials register (July 2004), the Cochrane Central Register of Controlled Trials (July 2004), MEDLINE (1966 to 2004), EMBASE (1980 to 2004), and CINAHL (1982 to 2004). We scanned secondary references and contacted experts in the field. SELECTION CRITERIA: All published and unpublished randomised controlled trials comparing an oestrogen and progestin intervention with a placebo or usual antepartum, intrapartum, or postpartum care among pregnant women or new mothers recruited within the first year postpartum. DATA COLLECTION AND ANALYSIS: Two review authors participated in the evaluation of methodological quality, data extraction, and data analysis. Results are presented using relative risk for categorical data and weighted mean difference for continuous data. MAIN RESULTS: Two trials, involving 229 women, met the selection criteria. Norethisterone enanthate, a synthetic progestogen, administered within 48 hours of delivery was associated with a significantly higher risk of developing postpartum depression. Oestrogen therapy was associated with a greater improvement in depression scores than placebo among women with severe depression. AUTHORS' CONCLUSIONS: Synthetic progestogens should be used with significant caution in the postpartum period. The role of natural progesterone in the prevention and treatment of postpartum depression has yet to be evaluated in a randomised, placebo-controlled trial. Oestrogen therapy may be of modest value for the treatment of severe postpartum depression. Its role in the prevention of recurrent postpartum depression has not been rigorously evaluated. Further research is warranted.

154Neuroendocrine Effects of Lactation and Hormone-Gene-Environment Interactions.PubMed

Kirsten Gust, Christina Caccese, Amanda Larosa, et al.
Mol Neurobiol. 2020 Apr;57(4):2074-2084. doi: 10.1007/s12035-019-01855-8. Epub 2020 Jan 11.
While correlational studies suggest that lactation may confer a certain level of protection from mental illness, this benefit is not uniformly expressed in all women who choose to breastfeed. We propose here that the neuroendocrine "resetting" induced by lactation may predispose toward positive affect states in a subset of hormone-sensitive mothers, with hormone-gene and hormone-environment interactions determining the ultimate psychological outcome. We find evidence to suggest that higher secretion of prolactin/oxytocin as well as lower secretion of vasopression/androgens in lactating mothers may protect against postpartum depression and anxiety, decrease levels of irritability, and optimize stress responses. On the other hand, while the abrupt withdrawal of estradiol/progesterone in the immediate postpartum period tends to be associated with adverse psychological outcomes, the chronic suppression of estrogens/progestogens induced by lactation may have antidepressant and anxiolytic effects over time. Finally, the hypo-cortisolemic state seen in lactating mothers appears to be associated with improved stress reactivity and circadian rhythms. We also discuss hormone-gene and hormone-environment interactions likely to modulate any potential psychological benefits related to lactation and focus on those factors that are either easy to screen for or known to be modifiable. In sum, neuroendocrine alterations induced by lactation may play a key role in determining reproductive psychiatric risk in a subset of hormone-sensitive women. Using these neuroendocrine factors as an individualized index of risk can help in devising targeted programs to support these women in pursuing lactation or, for those not able or willing, accessing psychological interventions in a timely manner.

155Non-psychotic mental disorders in the perinatal period.PubMed

Louise M Howard, Emma Molyneaux, Cindy-Lee Dennis, et al.
Lancet. 2014 Nov 15;384(9956):1775-88. doi: 10.1016/S0140-6736(14)61276-9. Epub 2014 Nov 14.
Mental disorders are among the most common morbidities of pregnancy and the postnatal period, and can have adverse effects on the mother, her child, and family. This Series paper summarises the evidence about epidemiology, risk factors, identification, and interventions for non-psychotic mental disorders. Although the phenomenology and risk factors for perinatal mental disorders are largely similar to those for the disorders at other times, treatment considerations differ during pregnancy and breastfeeding. Most randomised controlled trials have examined psychosocial and psychological interventions for postnatal depression, with evidence for effectiveness in treating and preventing the disorder. Few high-quality studies exist on the effectiveness or safety of pharmacological treatments in the perinatal period, despite quite high prescription rates. General principles of prescribing of drugs in the perinatal period are provided, but individual risk-benefit analyses are needed for decisions about treatment.

156Adolescents' electronic media use at night, sleep disturbance, and depressive symptoms in the smartphone age.PubMed

Sakari Lemola, Nadine Perkinson-Gloor, Serge Brand, et al.
J Youth Adolesc. 2015 Feb;44(2):405-18. doi: 10.1007/s10964-014-0176-x. Epub 2014 Sep 10.
Adolescence is a time of increasing vulnerability for poor mental health, including depression. Sleep disturbance is an important risk factor for the development of depression during adolescence. Excessive electronic media use at night is a risk factor for both adolescents' sleep disturbance and depression. To better understand the interplay between sleep, depressive symptoms, and electronic media use at night, this study examined changes in adolescents' electronic media use at night and sleep associated with smartphone ownership. Also examined was whether sleep disturbance mediated the relationship between electronic media use at night and depressive symptoms. 362 adolescents (12-17 year olds, M = 14.8, SD = 1.3; 44.8% female) were included and completed questionnaires assessing sleep disturbance (short sleep duration and sleep difficulties) and depressive symptoms. Further, participants reported on their electronic media use in bed before sleep such as frequency of watching TV or movies, playing video games, talking or text messaging on the mobile phone, and spending time online. Smartphone ownership was related to more electronic media use in bed before sleep, particularly calling/sending messages and spending time online compared to adolescents with a conventional mobile phone. Smartphone ownership was also related to later bedtimes while it was unrelated to sleep disturbance and symptoms of depression. Sleep disturbance partially mediated the relationship between electronic media use in bed before sleep and symptoms of depression. Electronic media use was negatively related with sleep duration and positively with sleep difficulties, which in turn were related to depressive symptoms. Sleep difficulties were the more important mediator than sleep duration. The results of this study suggest that adolescents might benefit from education regarding sleep hygiene and the risks of electronic media use at night.

157The prevalence and correlates of depression, anxiety, and stress in a sample of college students.PubMed

R Beiter, R Nash, M McCrady, et al.
J Affect Disord. 2015 Mar 1;173:90-6. doi: 10.1016/j.jad.2014.10.054. Epub 2014 Nov 8.
BACKGROUND: Over the past four years, the Franciscan University Counseling Center has reported a 231% increase in yearly visits, as well as a 173% increase in total yearly clients. This trend has been observed at many universities as mental health issues pose significant problems for many college students. The objective of this study was to investigate potential correlates of depression, anxiety, and stress in a sample of college students. METHODS: The final analyzed sample consisted of 374 undergraduate students between the ages of 18 and 24 attending Franciscan University, Steubenville, Ohio. Subjects completed a survey consisting of demographic questions, a section instructing participants to rate the level of concern associated with challenges pertinent to daily life (e.g. academics, family, sleep), and the 21 question version of the Depression Anxiety Stress Scale (DASS21). RESULTS: The results indicated that the top three concerns were academic performance, pressure to succeed, and post-graduation plans. Demographically, the most stressed, anxious, and depressed students were transfers, upperclassmen, and those living off-campus. CONCLUSIONS: With the propensity for mental health issues to hinder the success of college students, it is vital that colleges continually evaluate the mental health of their students and tailor treatment programs to specifically target their needs.

158Associations between obesogenic risk factors and depression among adolescents: a systematic review.PubMed

E Hoare, H Skouteris, M Fuller-Tyszkiewicz, et al.
Obes Rev. 2014 Jan;15(1):40-51. doi: 10.1111/obr.12069. Epub 2013 Aug 27.
Adolescence is a transitional life phase that is associated with heightened risk for two major health conditions - obesity and mental health problems. Given the established comorbidity of obesity and depression, one avenue that warrants further exploration is the association between obesogenic risk and obesity in the expression and maintenance of depressive symptoms. The aim of the current systematic review was to identify and evaluate the empirical literature reporting the relationships between obesogenic risk factors (physical activity, sedentary behaviour, diet and weight status) and depression in adolescents. A search of five databases for studies published over the last decade found 24 studies eligible for review. Relationships were found between lack of physical exercise, heightened sedentary behaviour, poor diet quality, obese or overweight and depression in adolescence. However, the finding that obesogenic risk factors are associated with poor adolescent mental health should be interpreted with caution as data typically come from non-representative samples with less than optimal study design and methodology.

159Adolescent Predictors of Deliberate Self-Harm Thoughts and Behavior Among Young Adults: A Longitudinal Cross-National Study.PubMed

Lindsay A Taliaferro, Jessica A Heerde, Jennifer A Bailey, et al.
J Adolesc Health. 2023 Jul;73(1):61-69. doi: 10.1016/j.jadohealth.2023.01.022. Epub 2023 Mar 11.
PURPOSE: This study builds upon and extends previous longitudinal research on deliberate self-harm (DSH) among youth by investigating which risk and protective factors during adolescence predict DSH thoughts and behavior in young adulthood. METHODS: Self-report data came from 1,945 participants recruited as state-representative cohorts from Washington State and Victoria, Australia. Participants completed surveys in seventh grade (average age 13 years), as they transitioned through eighth and ninth grades and online at age 25 years. Retention of the original sample at age 25 years was 88%. A range of risk and protective factors in adolescence for DSH thoughts and behavior in young adulthood were examined using multivariable analyses. RESULTS: Across the sample, 9.55% (n = 162) and 2.83% (n = 48) of young adult participants reported DSH thoughts and behaviors, respectively. In the combined risk-protective factor multivariable model for young adulthood DSH thoughts, depressive symptoms in adolescence (adjusted odds ratio [AOR] = 1.05; confidence interval [CI] = 1.00-1.09) increased risk, while higher levels of adolescent adaptive coping strategies (AOR = 0.46; CI = 0.28-0.74), higher levels of adolescent community rewards for prosocial behavior (AOR = 0.73; CI = 0.57-0.93), and living in Washington State decreased risk. In the final multivariable model for DSH behavior in young adulthood, less positive family management strategies during adolescence remained the only significant predictor (AOR = 1.90; CI = 1.01-3.60). DISCUSSION: DSH prevention and intervention programs should not only focus on managing depression and building/enhancing family connections and support but also promote resilience through efforts to promote adaptive coping and connections to adults within one's community who recognize and reward prosocial behavior.

160TikTok use and psychosocial factors among adolescents: Comparisons of non-users, moderate users, and addictive users.PubMed

Miao Chao, Jing Lei, Ru He, et al.
Psychiatry Res. 2023 Jul;325:115247. doi: 10.1016/j.psychres.2023.115247. Epub 2023 May 6.
Short-video applications like TikTok are increasingly popular. This study examines the association between short-video application use (SVU) and psychosocial factors in 1,346 adolescents (M = 14.97, 51.8% female). 199 non-users and 1147 users (686 moderate users, 461 addictive users) were identified. Results revealed a high prevalence of addictive SVU in the sample. Addictive users exhibited worse mental health conditions than non-users and moderate users, including higher levels of depression, anxiety, stress, loneliness, social anxiety, attention problems, and lower life satisfaction and sleep quality. Addictive users also faced higher academic stress, poorer academic performance, more bullying victimization, worse parental relationships, more negative parenting styles, and lower parental education levels. Moderate users had different family environments than non-users, but no differences in mental health or school performance. Together, these findings suggest that addictive users experience a more disadvantageous situation across mental health, family, and school conditions, while non-users have advantageous family environments. Moderate SVU may not be associated with negative mental health condition or poor school performance. Moderate and addictive SVU should be considered distinct phenomena. Given the psychiatric symptoms present in addictive users of TikTok and similar apps, targeted interventions and treatments are urgently needed.

161Depression in late life: review and commentary.PubMed

Dan G Blazer
J Gerontol A Biol Sci Med Sci. 2003 Mar;58(3):249-65. doi: 10.1093/gerona/58.3.m249.
Depression is perhaps the most frequent cause of emotional suffering in later life and significantly decreases quality of life in older adults. In recent years, the literature on late-life depression has exploded. Many gaps in our understanding of the outcome of late-life depression have been filled. Intriguing findings have emerged regarding the etiology of late-onset depression. The number of studies documenting the evidence base for therapy has increased dramatically. Here, I first address case definition, and then I review the current community- and clinic-based epidemiological studies. Next I address the outcome of late-life depression, including morbidity and mortality studies. Then I present the extant evidence regarding the etiology of depression in late life from a biopsychosocial perspective. Finally, I present evidence for the current therapies prescribed for depressed elders, ranging from medications to group therapy.

162Prevention of Incident and Recurrent Major Depression in Older Adults With Insomnia: A Randomized Clinical Trial.PubMed

Michael R Irwin, Carmen Carrillo, Nina Sadeghi, et al.
JAMA Psychiatry. 2022 Jan 1;79(1):33-41. doi: 10.1001/jamapsychiatry.2021.3422.
IMPORTANCE: Older adults with insomnia have a high risk of incident and recurrent depression. Depression prevention is urgently needed, and such efforts have been neglected for older adults. OBJECTIVE: To examine whether treatment of insomnia disorder with cognitive behavioral therapy for insomnia (CBT-I) compared with an active comparator condition, sleep education therapy (SET), prevents major depressive disorder in older adults. DESIGN, SETTING, AND PARTICIPANTS: This assessor-blinded, parallel-group, single-site randomized clinical trial assessed a community-based sample of 431 people and enrolled 291 adults 60 years or older with insomnia disorder who had no major depression or major health events in past year. Study recruitment was performed from July 1, 2012, to April 30, 2015. The trial protocol was modified to extend follow-up from 24 to 36 months, with follow-up completion in July 2018. Data analysis was performed from March 1, 2019, to March 30, 2020. INTERVENTIONS: Participants were randomized to 2 months of CBT-I (n = 156) or SET (n = 135). MAIN OUTCOMES AND MEASURES: The primary outcome was time to incident major depressive disorder as diagnosed by interview and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. Secondary outcome was sustained remission of insomnia disorder before depression event or duration of follow-up. RESULTS: Among 291 randomized participants (mean [SD] age, 70.1 [6.7] years; 168 [57.7%] female; 7 [2.4%] Asian, 32 [11.0%] Black, 3 [1.0%] Pacific Islander, 241 [82.8%] White, 6 [2.1%] multiracial, and 2 [0.7%] unknown), 156 were randomized to CBT-I and 135 to SET. A total of 140 participants (89.7%) completed CBT-I and 130 (96.3%) participants completed SET (χ2 = 4.9, P = .03), with 114 (73.1%) completing 24 months of follow-up in the CBT-I group and 117 (86.7%) in the SET group (χ2 = 8.4, P = .004). After protocol modification, 92 (59.0%) of the CBT-I participants and 86 (63.7%) of the SET participants agreed to extended follow-up (χ2 = 0.7, P = .41), with 81 (51.9%) of the CBT-I participants and 77 (57.0%) of the SET group completing 36 months of follow-up (χ2 = 0.8; P = .39). Incident or recurrent major depression occurred in 19 participants (12.2%) in the CBT-I group and in 35 participants (25.9%) in the SET group, with an overall benefit (hazard ratio, 0.51; 95%, CI 0.29-0.88; P = .02) consistent across subgroups. Remission of insomnia disorder continuously sustained before depression event or during follow-up was more likely in CBT-I participants (41 [26.3%]) compared with the SET participants (26 [19.3%], P = .03). Those in the CBT-I group with sustained remission of insomnia disorder had an 82.6% decreased likelihood of depression (hazard ratio, 0.17; 95%, CI 0.04-0.73; P = .02) compared with those in the SET group without sustained remission of insomnia disorder. CONCLUSIONS AND RELEVANCE: The findings of this randomized clinical trial indicate that treatment of insomnia with CBT-I has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder. Community-level screening for insomnia concerns in older adults and wide delivery of CBT-I-based treatment for insomnia could substantially advance public health efforts to treat insomnia and prevent depression in this vulnerable older adult population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01641263.

163Research progress on the mechanism of exercise against depression.PubMed

Ya-Lin Zhao, Shu-Ya Sun, Hao-Cheng Qin, et al.
World J Psychiatry. 2024 Nov 19;14(11):1611-1617. doi: 10.5498/wjp.v14.i11.1611.
The substantial global health burden of depression encourages the development of innovative and broadly effective interventions. This paper aimed to examine recent advancements by which exercise works as an antidepressant and recommends optimal types and quantity of exercise as supplemental therapies in treating depression. Sedentary behavior and low physical activity significantly influence the onset of depression. Being an effective treatment option, exercise can significantly reduce depression risk. Exercise exerts antidepressant effects as it modulates neurotransmitters, neuroplasticity, the immune system, and hormone levels. Effective exercise forms include yoga, strength training, and walking/jogging. Tailored exercise regimens that consider individual preferences and tolerability can improve outcomes. Regular exercise enhances general well-being and reduces depressive symptoms. Additional research is needed to understand the complex basis of exercise's effects on depression. Exercise is a cost-effective and accessible intervention for depression management that needs additional exploration. Thus, customized exercise programs, as per each patient's needs, are essential for their successful implementation clinically.

164Adolescents' Physical Activity and Depressive Symptoms: A Psychosocial Mechanism.PubMed

Liang Shen, Xiangli Gu, Tao Zhang, et al.
Int J Environ Res Public Health. 2022 Jan 24;19(3):1276. doi: 10.3390/ijerph19031276.
Guided by the Theory of Planned Behavior (TPB; Ajzen, 1991), this study aimed to test a hypothesized path model of TPB variables (i.e., attitude toward behavior, subjective norm, perceived behavioral control, and intention) with physical activity (PA) and depressive symptoms. A total of 792 Chinese adolescents ( = 16.9; = 0.82; 54.5% females) completed previously validated questionnaires assessing their TPB variables, PA, and depressive symptoms. Correlation analysis revealed TPB variables were positively associated with PA ( < 0.01), and negatively correlated to depressive symptoms ( < 0.01). The path analyses indicated that the hypothesized model produces a goodness of fit (χ/df = 16.14/5, CFI = 0.99, RMSEA = 0.06). The findings support the theoretical tenets of TPB and provide empirical evidence of the psychosocial mechanism of PA and depressive symptoms in Chinese adolescents. It suggests that building PA intervention strategies while considering the TPB framework may promote adolescents' physical and mental health.

165Assessing BDNF as a mediator of the effects of exercise on depression.PubMed

Kristin L Szuhany, Michael W Otto
J Psychiatr Res. 2020 Apr;123:114-118. doi: 10.1016/j.jpsychires.2020.02.003. Epub 2020 Feb 8.
Brain-derived neurotrophic factor (BDNF) is associated with neuronal growth and reduced BDNF has been implicated in depression. A recent meta-analysis documented reliable effects of exercise on BDNF levels (Szuhany et al., 2015); although, few studies included participants with mental health conditions. In this study, we examine whether increased exercise was associated with enhanced BDNF response in depressed patients, and whether this change mediated clinical benefits. A total of 29 depressed, sedentary participants were randomized to receive either behavioral activation (BA) plus an exercise or stretching prescription. Blood was collected prior to (resting BDNF levels) and following an exercise test (pre-to post-exercise BDNF change) at four points throughout the study. Participants also completed depression and exercise assessments. BDNF increased significantly across all assessment points (p < 0.001, d = 0.83). Changes in BDNF from pre-to post-exercise were at a moderate effect for the interaction of exercise and time which did not reach significance (p = 0.13, d = 0.53), with a similar moderate, non-significant effect for resting BDNF levels (p = 0.20, d = 0.49). Contrary to hypotheses, change in resting BDNF or endpoint change in BDNF was not associated with changes in depression. In an intervention that included active treatment (BA), we could not verify an independent predictive effect for changes in BDNF across the trial. Overall, this study adds to the literature showing reliable effects of acute exercise on increasing BDNF and extends this research to the infrequently studied depressed population, but does not clarify the mechanism behind exercise benefits for depression. CLINICAL TRIALS REGISTRY (CLINICALTRIALS.GOV): NCT02176408, "Efficacy of Adjunctive Exercise for the Behavioral Treatment of Major Depression".

166Diet and depression: exploring the biological mechanisms of action.PubMed

Wolfgang Marx, Melissa Lane, Meghan Hockey, et al.
Mol Psychiatry. 2021 Jan;26(1):134-150. doi: 10.1038/s41380-020-00925-x. Epub 2020 Nov 3.
The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression onset and symptom management. To guide future clinical trials and targeted dietary therapies, this review provides an overview of what is currently known regarding underlying mechanisms of action by which diet may influence mental and brain health. The mechanisms of action associating diet with health outcomes are complex, multifaceted, interacting, and not restricted to any one biological pathway. Numerous pathways were identified through which diet could plausibly affect mental health. These include modulation of pathways involved in inflammation, oxidative stress, epigenetics, mitochondrial dysfunction, the gut microbiota, tryptophan-kynurenine metabolism, the HPA axis, neurogenesis and BDNF, epigenetics, and obesity. However, the nascent nature of the nutritional psychiatry field to date means that the existing literature identified in this review is largely comprised of preclinical animal studies. To fully identify and elucidate complex mechanisms of action, intervention studies that assess markers related to these pathways within clinically diagnosed human populations are needed.

167The impact of Otago exercise programme on the prevention of falls in older adult: A systematic review.PubMed

Yi Yang, Kun Wang, Hengxu Liu, et al.
Front Public Health. 2022 Oct 20;10:953593. doi: 10.3389/fpubh.2022.953593. eCollection 2022.
OBJECTIVE: To improve the quality of life of older adult in their later years, by increasing the physical activity participation of older adult, the occurrence of falls accident scores in older adult can be prevented. This paper comprehensively summarizes the origin, development, participation forms, and fitness effects of the Otago exercise program (OEP). METHODS: Using PubMed, web of science, CNKI, dimensional spectrum, and other databases, search for research papers from 2005 to April 2021 by using keywords such as Otago project exercise; aged, Fall; Cognitive function, Balance ability, Lower limb strength, Fall efficiency, and so on. PEDro Scale was used to check the quality of the literatures. RESULTS: A total of 34 papers were included after searching for kinds of literature related to the subject of this paper and after careful review by researchers. CONCLUSIONS: Otago exercise programme is beneficial to improve the cognitive function of older adult, enhance their lower limb muscle strength and dynamic and static balance ability, and then improve the gait stability and posture control ability of older adult, which has significant positive benefits for the prevention of falls in older adult. OEP is helpful to improve the falling efficiency of older adult, help older adult overcome the fear of falling, and form a positive emotion of "exercise improves exercise," to reduce the harm caused by sedentary behavior and the incidence of depression and improve their subjective wellbeing. Although OEP has significant positive effects on improving the health and physical fitness of older adult, preventing falls, and restoring clinical function, the corresponding neural mechanism for preventing falls is not very clear. At the same time, how OEP can be combined with emerging technologies to maximize its benefits needs to be further discussed in the future.

168Depression in sleep disturbance: A review on a bidirectional relationship, mechanisms and treatment.PubMed

Hong Fang, Sheng Tu, Jifang Sheng, et al.
J Cell Mol Med. 2019 Apr;23(4):2324-2332. doi: 10.1111/jcmm.14170. Epub 2019 Feb 7.
Sleep disturbance is the most prominent symptom in depressive patients and was formerly regarded as a main secondary manifestation of depression. However, many longitudinal studies have identified insomnia as an independent risk factor for the development of emerging or recurrent depression among young, middle-aged and older adults. This bidirectional association between sleep disturbance and depression has created a new perspective that sleep problems are no longer an epiphenomenon of depression but a predictive prodromal symptom. In this review, we highlight the treatment of sleep disturbance before, during and after depression, which probably plays an important role in improving outcomes and preventing the recurrence of depression. In clinical practice, pharmacological therapies, including hypnotics and antidepressants, and non-pharmacological therapies are typically applied. A better understanding of the pathophysiological mechanisms between sleep disturbance and depression can help psychiatrists better manage this comorbidity.

169Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies.PubMed

Chiara Baglioni, Gemma Battagliese, Bernd Feige, et al.
J Affect Disord. 2011 Dec;135(1-3):10-9. doi: 10.1016/j.jad.2011.01.011. Epub 2011 Feb 5.
BACKGROUND: In many patients with depression, symptoms of insomnia herald the onset of the disorder and may persist into remission or recovery, even after adequate treatment. Several studies have raised the question whether insomniac symptoms may constitute an independent clinical predictor of depression. This meta-analysis is aimed at evaluating quantitatively if insomnia constitutes a predictor of depression. METHODS: PubMed, Medline, PsycInfo, and PsycArticles databases were searched from 1980 until 2010 to identify longitudinal epidemiological studies simultaneously investigating insomniac complaints and depressed psychopathology. Effects were summarized using the logarithms of the odds ratios for insomnia at baseline to predict depression at follow-up. Studies were pooled with both fixed- and random-effects meta-analytic models in order to evaluate the concordance. Heterogeneity test and sensitivity analysis were computed. RESULTS: Twenty-one studies met inclusion criteria. Considering all studies together, heterogeneity was found. The random-effects model showed an overall odds ratio for insomnia to predict depression of 2.60 (confidence interval [CI]: 1.98-3.42). When the analysis was adjusted for outliers, the studies were not longer heterogeneous. The fixed-effects model showed an overall odds ratio of 2.10 (CI: 1.86-2.38). LIMITATIONS: The main limit is that included studies did not always consider the role of other intervening variables. CONCLUSIONS: Non-depressed people with insomnia have a twofold risk to develop depression, compared to people with no sleep difficulties. Thus, early treatment programs for insomnia might reduce the risk for developing depression in the general population and be considered a helpful general preventive strategy in the area of mental health care.

170Chronic insomnia, REM sleep instability and emotional dysregulation: A pathway to anxiety and depression?PubMed

Dieter Riemann, Raphael J Dressle, Fee Benz, et al.
J Sleep Res. 2025 Apr;34(2):e14252. doi: 10.1111/jsr.14252. Epub 2024 May 29.
The world-wide prevalence of insomnia disorder reaches up to 10% of the adult population. Women are more often afflicted than men, and insomnia disorder is a risk factor for somatic and mental illness, especially depression and anxiety disorders. Persistent hyperarousals at the cognitive, emotional, cortical and/or physiological levels are central to most theories regarding the pathophysiology of insomnia. Of the defining features of insomnia disorder, the discrepancy between minor objective polysomnographic alterations of sleep continuity and substantive subjective impairment in insomnia disorder remains enigmatic. Microstructural alterations, especially in rapid eye movement sleep ("rapid eye movement sleep instability"), might explain this mismatch between subjective and objective findings. As rapid eye movement sleep represents the most highly aroused brain state during sleep, it might be particularly prone to fragmentation in individuals with persistent hyperarousal. In consequence, mentation during rapid eye movement sleep may be toned more as conscious-like wake experience, reflecting pre-sleep concerns. It is suggested that this instability of rapid eye movement sleep is involved in the mismatch between subjective and objective measures of sleep in insomnia disorder. Furthermore, as rapid eye movement sleep has been linked in previous works to emotional processing, rapid eye movement sleep instability could play a central role in the close association between insomnia and depressive and anxiety disorders.

171Moderators of Cognitive Behavioral Treatment for Insomnia on Depression and Anxiety Outcomes.PubMed

Riya Mirchandaney, Raul Barete, Lauren D Asarnow
Curr Psychiatry Rep. 2022 Feb;24(2):121-128. doi: 10.1007/s11920-022-01326-3. Epub 2022 Jan 21.
PURPOSE OF REVIEW: With a focus on reviewing adequately powered randomized controlled trials, we present recent research on the potential of cognitive behavioral therapy for insomnia (CBT-I) to improve depression and anxiety outcomes among patients with insomnia and one of the following comorbid psychiatric disorders: major depressive disorder (MDD), generalized anxiety disorder (GAD), or posttraumatic stress disorder (PTSD). We also examine potential moderators of CBT-I on depression and anxiety outcomes in this population. RECENT FINDINGS: Despite high comorbidity rates, current behavioral and pharmacological treatments for MDD, GAD, and PTSD do not substantially target or improve insomnia symptoms; residual insomnia is exceedingly common even among patients who experience remission. Insomnia plays a critical role in the onset and maintenance of depression and anxiety, and treating insomnia with CBT-I may improve global outcomes for patients with MDD, GAD, and PTSD. CBT-I is superior to traditional depression/anxiety treatment in improving insomnia symptoms among patients with comorbid psychiatric disorders. Results are mixed on whether CBT-I (either alone or augmented with depression/anxiety treatment) is effective in improving overall MDD, GAD, and PTSD outcomes. Evening circadian preference and depression/anxiety symptom severity may moderate the effect of CBT-I on depression and anxiety outcomes.

172Psychological Treatment of Comorbid Insomnia and Depression: A Double-Blind Randomized Placebo-Controlled Trial.PubMed

Kerstin Blom, Erik Forsell, Monica Hellberg, et al.
Psychother Psychosom. 2024;93(2):100-113. doi: 10.1159/000536063. Epub 2024 Jan 29.
INTRODUCTION: Insomnia and depression are highly prevalent disorders and commonly occur together. Cognitive behavioral therapy for insomnia, CBT-I, has been shown to be effective in treating insomnia and also comorbid depression. However, it is unclear whether effects of CBT-I on depression are specific or nonspecific. Also, depressive symptoms often remain too high after CBT-I, indicating a need for improved treatments. The objective was to determine whether combining CBT-I with CBT for depression, without increasing treatment length, reduces both insomnia and depression more than CBT for depression with a placebo insomnia intervention. METHODS: A 12-week double-blind randomized controlled trial with a 6-month follow-up in a psychiatric setting using therapist-guided internet-delivered treatments was conducted. Patients (N = 126) were diagnosed with insomnia disorder and major depression by physicians. Primary outcome measures were as follows: self-rating scales Insomnia Severity Index (ISI) and Montgomery-Åsberg Depression Rating Scale (MADRS-S). RESULTS: The combined treatment showed specific effects on insomnia severity over the control treatment (p = 0.007) but was not more effective in reducing depression severity. Within-group effects (Cohen's d) at post and at 6 months were as follows: ISI 1.40 and 1.42 (combined treatment), 0.95 and 1.00 (control); MADRS-S 0.97 and 1.12 (combined), 0.88 and 0.89 (control). CONCLUSIONS: CBT-I shows large specific effects on insomnia severity and is superior to control in this regard. Both treatments had similar effects on depression severity, i.e., combining CBT-I with CBT for depression did not enhance outcomes on depression compared to control. We suggest CBT-I should always be offered to patients with insomnia and depression comorbidity, possibly as the first-hand choice. Combining it with a psychological treatment for depression could be too burdening and may not be beneficial.

173Diet quality and depression risk: A systematic review and dose-response meta-analysis of prospective studies.PubMed

Marc Molendijk, Patricio Molero, Felipe Ortuño Sánchez-Pedreño, et al.
J Affect Disord. 2018 Jan 15;226:346-354. doi: 10.1016/j.jad.2017.09.022. Epub 2017 Sep 23.
BACKGROUND: It has been claimed that the quality of a diet is associated with the incidence of depressive disorders. We sought to investigate the evidence for this claim. METHODS: Systematic searches were performed up to March 6th, 2017 in order to identify prospective cohort studies that reported on exposure to dietary patterns or food groups and the incidence of depression/depressive symptoms. Data from 24 independent cohorts (totalling 1,959,217 person-years) were pooled in random-effects meta-analyses. RESULTS: Adherence to a high-quality diet, regardless of type (i.e., healthy/prudent or Mediterranean), was associated with a lower risk of depressive symptoms over time (odds ratios ranged 0.64-0.78 in a linear dose-response fashion [P < 0.01]). A relatively low dietary inflammatory index was also associated with a somewhat lower incidence of depressive symptom (odds ratio = 0.81), although not in a dose-response fashion. Similar associations were found for the consumption of fish and vegetables (odds ratios 0.86 and 0.82 respectively) but not for other high quality food groups (e.g., fruit). Studies that controlled for depression severity at baseline or that used a formal diagnosis as outcome did not yield statistically significant findings. Adherence to low quality diets and food groups was not associated with higher depression incidence. LIMITATIONS: Our ability to detect confounders was only limited. CONCLUSION: There is evidence that a higher quality of a diet is associated with a lower risk for the onset of depressive symptoms, but not all available results are consistent with the hypothesis that diet influences depression risk. Prospective studies that control for relevant confounders such as obesity incidence and randomized controlled prevention trials are needed to increase the validity of findings in this field.

174Association of Western and traditional diets with depression and anxiety in women.PubMed

Felice N Jacka, Julie A Pasco, Arnstein Mykletun, et al.
Am J Psychiatry. 2010 Mar;167(3):305-11. doi: 10.1176/appi.ajp.2009.09060881. Epub 2010 Jan 4.
OBJECTIVE: Key biological factors that influence the development of depression are modified by diet. This study examined the extent to which the high-prevalence mental disorders are related to habitual diet in 1,046 women ages 20-93 years randomly selected from the population. METHOD: A diet quality score was derived from answers to a food frequency questionnaire, and a factor analysis identified habitual dietary patterns. The 12-item General Health Questionnaire (GHQ-12) was used to measure psychological symptoms, and a structured clinical interview was used to assess current depressive and anxiety disorders. RESULTS: After adjustments for age, socioeconomic status, education, and health behaviors, a "traditional" dietary pattern characterized by vegetables, fruit, meat, fish, and whole grains was associated with lower odds for major depression or dysthymia and for anxiety disorders. A "western" diet of processed or fried foods, refined grains, sugary products, and beer was associated with a higher GHQ-12 score. There was also an inverse association between diet quality score and GHQ-12 score that was not confounded by age, socioeconomic status, education, or other health behaviors. CONCLUSIONS: These results demonstrate an association between habitual diet quality and the high-prevalence mental disorders, although reverse causality and confounding cannot be ruled out as explanations. Further prospective studies are warranted.

175An anti-inflammatory diet as a potential intervention for depressive disorders: A systematic review and meta-analysis.PubMed

Katie Tolkien, Steven Bradburn, Chris Murgatroyd
Clin Nutr. 2019 Oct;38(5):2045-2052. doi: 10.1016/j.clnu.2018.11.007. Epub 2018 Nov 20.
BACKGROUND & AIMS: There is a large body of evidence which supports the role of inflammation in the pathophysiology of mental health disorders, including depression. Dietary patterns have been shown to modulate the inflammatory state, thus highlighting their potential as a therapeutic tool in disorders with an inflammatory basis. Here we conduct a systematic review and meta-analysis of current literature addressing whether there is a link between the inflammatory potential of a diet and risk of depression or depressive symptoms. METHODS: A systematic literature search was performed to identify studies that reported an association between the inflammatory potential of the diet and risk of depressive symptoms or diagnosis of depression. Random effect models were used to meta-analyse effect sizes. Quality assessment, publication bias, sensitivity and subgroup analyses were also performed. RESULTS: Eleven studies, with a total of 101,950 participants at baseline (age range: 16-72 years old), were eligible for review. A significant association between a pro-inflammatory diet and increased risk of depression diagnosis or symptoms was evident, relative to those on an anti-inflammatory diet (OR: 1.40, 95% confidence intervals: 1.21-1.62, P < 0.001). No publication bias was detected; however, some study heterogeneity was evident (I = 63%, P < 0.001). Subgroup analyses suggested the main source of study heterogeneity was the study design (cross-sectional or longitudinal) and the effect measure used (odds ratio, hazard ratio or relative risk). CONCLUSION: These results provide an association between pro-inflammatory diet and risk of depression. Thus, adopting an anti-inflammatory diet may be an effective intervention or preventative means of reducing depression risk and symptoms.

176High-fiber diet ameliorates gut microbiota, serum metabolism and emotional mood in type 2 diabetes patients.PubMed

Lihua Chen, Bo Liu, Lixia Ren, et al.
Front Cell Infect Microbiol. 2023 Jan 30;13:1069954. doi: 10.3389/fcimb.2023.1069954. eCollection 2023.
Previous studies have demonstrated that patients with type 2 diabetes mellitus (T2DM) often had the problems of fecal microbiota dysbiosis, and were usually accompanied with psychiatric comorbidities (such as depression and anxiety). Here, we conducted a randomized clinical study to analyze the changes in gut microbiota, serum metabolism and emotional mood of patients with T2DM after consumption of a high-fiber diet. The glucose homeostasis of participants with T2DM was improved by the high-fiber diet, and the serum metabolome, systemic inflammation and psychiatric comorbidities were also altered. The increased abundances of , and revealed that the proportions of beneficial gut microbes were enriched by the high-fiber diet, while the abundances of , and other opportunistic pathogens were decreased. Therefore, the current study demonstrated that the intestinal microbiota alterations which were influenced by the high-fiber diet could improve the serum metabolism and emotional mood of patients with T2DM.

177Association between dietary patterns and suicide ideation among depressed adults: Insights from NHANES 2007-2020.PubMed

Kun Li, Honggang Lyu, Lihong Zhang, et al.
J Affect Disord. 2025 May 15;377:235-244. doi: 10.1016/j.jad.2025.02.073. Epub 2025 Feb 21.
BACKGROUND: Dietary patterns are strongly linked to the risk of major depressive disorder (MDD). However, research on the relationship between dietary patterns and MDD with suicidal ideation (MDD + SI) are limited. The Healthy Eating Index (HEI)-2015, Dietary Inflammatory Index (DII), Comprehensive Dietary Antioxidant Index (CDAI), Oxidative Balance Score (OBS), and Dietary Index for Gut Microbiota (DI-GM) are five validated tools for assessing dietary patterns based on inflammation, antioxidant capacity, and gut microbiota diversity. This study aims to investigate the association between these dietary indices and MDD + SI. METHODS: A total of 23,621 participants from the 2007-2020 National Health and Nutrition Examination Survey were included in this study. MDD and SI were assessed using the PHQ-9. Weighted multivariable logistic regression, subgroup analyses, and restricted cubic spline (RCS) models were applied to analyze the relationships between five dietary indices and the risks of MDD and MDD + SI. RESULTS: All five dietary indices showed associations with MDD to varying degrees; however, only DI-GM exhibited a significant negative association with MDD + SI after adjustment for confounding factors. Subgroup and stratified linear trend analyses revealed that this association was stronger among former smokers, obese individuals and those with hypertension or diabetes. RCS analysis showed a significant non-linear relationship between DI-GM and MDD, while a significant linear dose-response relationship was observed for DI-GM and MDD + SI. LIMITATIONS: Cross-sectional study designs cannot establish causality. CONCLUSION: The findings of this study revealed a significant association between DI-GM and MDD + SI. Dietary interventions that promote gut microbiota diversity may help reduce the risk of MDD + SI.

178Diet, Stress and Mental Health.PubMed

J Douglas Bremner, Kasra Moazzami, Matthew T Wittbrodt, et al.
Nutrients. 2020 Aug 13;12(8):2428. doi: 10.3390/nu12082428.
INTRODUCTION: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. METHODS: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. RESULTS: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. CONCLUSIONS: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.

179Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.PubMed

Chong-Su Kim, Lina Cha, Minju Sim, et al.
J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):32-40. doi: 10.1093/gerona/glaa090.
Probiotics have been proposed to ameliorate cognitive impairment and depressive disorder via the gut-brain axis in patients and experimental animal models. However, the beneficial role of probiotics in brain functions of healthy older adults remains unclear. Therefore, a randomized, double-blind, and placebo-controlled multicenter trial was conducted to determine the effects of probiotics on cognition and mood in community-dwelling older adults. Sixty-three healthy elders (≥65 years) consumed either placebo or probiotics containing Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI for 12 weeks. The gut microbiota was analyzed using 16S rRNA sequencing and bioinformatics. Brain functions were measured using the Consortium to Establish a Registry for Alzheimer's disease, Satisfaction with life scale, stress questionnaire, Geriatric depression scale, and Positive affect and negative affect schedule. Blood brain-derived neurotrophic factor (BDNF) was determined using enzyme-linked immunosorbent assay. Relative abundance of inflammation-causing gut bacteria was significantly reduced at Week 12 in the probiotics group (p < .05). The probiotics group showed greater improvement in mental flexibility test and stress score than the placebo group (p < .05). Contrary to placebo, probiotics significantly increased serum BDNF level (p < .05). Notably, the gut microbes significantly shifted by probiotics (Eubacterium and Clostridiales) showed significant negative correlation with serum BDNF level only in the probiotics group (RS = -0.37, RS = -0.39, p < .05). In conclusion, probiotics promote mental flexibility and alleviate stress in healthy older adults, along with causing changes in gut microbiota. These results provide evidence supporting health-promoting properties of probiotics as a part of healthy diet in the older adults.

180Dietary Patterns and Major Depression: Results from 15,262 Participants (International ALIMENTAL Study).PubMed

Yannis Achour, Guillaume Lucas, Sylvain Iceta, et al.
Nutrients. 2025 May 4;17(9):1583. doi: 10.3390/nu17091583.
BACKGROUND: Different patterns of food consumption may be associated with a differential risk of depression. Differences in dietary patterns between men and women and across different age groups have been reported, but their influence on the risk of depression has not been fully explored. OBJECTIVES: To investigate the associations between dietary patterns and risk of depression across sex and age groups to identify vulnerable subpopulations, which may inform targeted prevention and intervention strategies. METHODS: The ALIMENTAL study was a cross-sectional, online international survey conducted between 2021 and 2023. Dietary data were collected using a validated food frequency questionnaire; depression data were collected using a self-reported validated questionnaire. Principal component analysis (PCA) was applied to identify distinct food consumption patterns. Multivariate analyses were then conducted to assess the associations between these patterns and depression, adjusting for multiple potential confounders. RESULTS: Among 15,262 participants without chronic diseases or current psychotropic treatments, 4923 (32.2%) were classified in the depression group. Among those aged 18-34, the PCA-derived factor of ultra-processed foods consumption was significantly associated with increased risk of depression in both sexes with similar odds ratios (women 1.21, 95% confidence interval (CI): (1.15; 1.27), men 1.21, 95% CI: (1.07-1.18)). In women aged 18-34, the PCA factors for sodas (aOR 1.10, 95% CI: (1.06; 1.95) and canned and frozen foods (aOR 1.10, 95% CI: (1.04; 1.15) were associated with an increased risk of depression. In participants aged 35-54 years, the association between ultra-processed foods and depression was only observed in women (35-54 years: aOR 1.30, 95% CI: (1.20; 1.42), ≥55 years: 1.41, 95% CI: (1.11; 1.79)), with a significant association between a higher adherence to the PCA-derived "healthy diet" factor (e.g., fruits, nuts, green vegetables) and a lower risk of depression (35-54 years: aOR 0.82, 95% CI: (0.75; 0.89), ≥55 years: aOR 0.79, 95% CI: (0.64; 0.97)). CONCLUSIONS: These results show significant differences between men and women and between age groups regarding associations between dietary patterns and the risk of depression. These findings can help better target public health interventions.

181Ambient Air Pollution Increases the Risk of Cerebrovascular and Neuropsychiatric Disorders through Induction of Inflammation and Oxidative Stress.PubMed

Omar Hahad, Jos Lelieveld, Frank Birklein, et al.
Int J Mol Sci. 2020 Jun 17;21(12):4306. doi: 10.3390/ijms21124306.
Exposure to ambient air pollution is a well-established determinant of health and disease. The Lancet Commission on pollution and health concludes that air pollution is the leading environmental cause of global disease and premature death. Indeed, there is a growing body of evidence that links air pollution not only to adverse cardiorespiratory effects but also to increased risk of cerebrovascular and neuropsychiatric disorders. Despite being a relatively new area of investigation, overall, there is mounting recent evidence showing that exposure to multiple air pollutants, in particular to fine particles, may affect the central nervous system (CNS) and brain health, thereby contributing to increased risk of stroke, dementia, Parkinson's disease, cognitive dysfunction, neurodevelopmental disorders, depression and other related conditions. The underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests inflammation and oxidative stress to be crucial factors in the pathogenesis of air pollution-induced disorders, driven by the enhanced production of proinflammatory mediators and reactive oxygen species in response to exposure to various air pollutants. From a public health perspective, mitigation measures are urgent to reduce the burden of disease and premature mortality from ambient air pollution.

182Association of air pollutants with psychiatric disorders: a two-sample Mendelian randomization.PubMed

Yuan-Yuan Ma, Qiong-Yan Li, An-Yu Shi, et al.
Ecotoxicol Environ Saf. 2024 Oct 15;285:117105. doi: 10.1016/j.ecoenv.2024.117105. Epub 2024 Sep 26.
BACKGROUND: The link between air pollution and increased risk of psychiatric disorders has been growing in evidence. However, the causal relationship between air pollution and psychiatric disorders remains poorly understood. METHODS: Single-nucleotide polymorphisms associated with air pollutants (including NOx, NO, PM, PM, and PM) from the UK Biobank were used as instrumental variables. Summary-level data for psychiatric disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, and obsessive-compulsive disorder) were procured from the Psychiatric Genomics Consortium and FinnGen consortium. Two-sample Mendelian randomization (MR) analysis was conducted to analyze the causal associations. RESULTS: The MR analysis revealed significant associations between certain air pollutants and specific types of psychiatric disorders. The inverse-variance weighted model of preliminary analysis indicated that genetically predicted NO was associated with increased risks of major depressive disorder (odds ratio [OR]: 1.13, 95 % confidence intervals [CI]: 1.00-1.28, P = 0.041), bipolar disorder (OR: 1.26, 95 % CI: 1.00-1.58, P = 0.0497), schizophrenia (OR: 1.57, 95 % CI: 1.23-2.00, P < 0.001), attention deficit hyperactivity disorder (OR: 1.61, 95 % CI: 1.25-2.09, P < 0.001) and autism spectrum disorder (OR: 1.39, 95 % CI: 1.01-1.91, P = 0.044). Genetically predicted PM showed a positive association with the risk of major depressive disorder (OR: 1.21, 95 % CI: 1.06-1.39, P = 0.006), bipolar disorder (OR: 1.32, 95 % CI: 1.03-1.69, P = 0.030) and attention deficit hyperactivity disorder (OR: 1.57, 95 % CI: 1.16-2.12, P = 0.004). In addition, our results also indicated that NOx (OR: 1.64, 95 % CI: 1.21-2.21, P = 0.0012) and PM (OR: 1.70, 95 % CI: 1.23-2.36, P = 0.0014) could increase the risk of attention deficit hyperactivity disorder. CONCLUSIONS: The MR analysis provides evidence for the causality of different air pollutants on specific psychiatric disorders, underscoring the importance of mitigating air pollution to reduce the risk of psychiatric disorders.

183Ambient PM2.5 caused depressive-like responses through Nrf2/NLRP3 signaling pathway modulating inflammation.PubMed

Chen Chu, Haiya Zhang, Shijie Cui, et al.
J Hazard Mater. 2019 May 5;369:180-190. doi: 10.1016/j.jhazmat.2019.02.026. Epub 2019 Feb 10.
PM2.5 pollution has been associated with numerous adverse effects including cardiovascular, respiratory and metabolic diseases as well as emotional disorders. However, the potential mechanism has not known clearly. Twenty-four rats were divided into 3 groups and exposed to various airs: filtered air (FA), unfiltered air (UA) and concentrated PM2.5 air (CA), respectively. Thirty wild type (WT) and 30 Nrf2 knockout (KO) mice were divided into 2 groups and exposed to FA and UA, respectively. The changes of neurobehavioral function, neurotransmitter secretion, toxic elements deposition, oxidative stress and the inflammation in prefrontal cortex were investigated during 9-12 weeks with/without PM2.5 exposure. Results showed that CA rats and KO-UA mice emerged obviously depressive-like responses. Li, Be, Al, Cr, Co, Ni, Se, Cd, Ba, Ti and Pb could deposit in the prefrontal cortex of rats after PM2.5 exposure. The neurotransmitters were significantly disorder in prefrontal cortex of CA rats. The NLRP3 signaling pathway was more activated in Nrf2 than WT mice after PM2.5 exposure for 9 weeks. Nrf2/ NLRP3 signaling pathway modulating the inflammation might play an important role in the depression induced by ambient PM2.5.

184[Impact of environmental risk factors such as noise and air pollution on mental health: What do we know?].PubMed

Omar Hahad, Manfred E Beutel, Donya A Gilan, et al.
Dtsch Med Wochenschr. 2020 Nov;145(23):1701-1707. doi: 10.1055/a-1201-2155. Epub 2020 Aug 5.
An increasing number of studies underlines the role of noise and air pollution as important environmental risk factors. It is unclear, how noise and air pollution impact mental health. Current study results indicate that environmental noise (in particular traffic noise) and various components of air pollution (in particular particulate matter) can increase the risk of mental disorders such as depression, anxiety disorders, psychoses and suicide. Pathophysiological mechanisms include both biological (such as oxidative stress and inflammation) and psychosocial factors (such as mental stress). Environmental risk factors such as noise and air pollution can have a significant impact on mental health. Due to the partly heterogeneous study results and the limited availability of methodically high-quality longitudinal studies, further studies are absolutely necessary, which allow deeper insights into these relationships.

185Environmental Pollution to Blame for Depressive Disorder?PubMed

Mariana Segovia-Mendoza, Margarita Isabel Palacios-Arreola, Lenin Pavón, et al.
Int J Environ Res Public Health. 2022 Feb 2;19(3):1737. doi: 10.3390/ijerph19031737.
Public concern has emerged about the effects of endocrine-disrupting compounds (EDCs) on neuropsychiatric disorders. Preclinical evidence suggests that exposure to EDCs is associated with the development of major depressive disorder (MDD) and could result in neural degeneration. The interaction of EDCs with hormonal receptors is the best-described mechanism of their biological activity. However, the dysregulation of the hypothalamic-pituitary-gonadal adrenal axis has been reported and linked to neurological disorders. At a worldwide level and in Mexico, the incidence of MDD has recently been increasing. Of note, in Mexico, there are no clinical associations on blood levels of EDCs and the incidence of the MDD. Methodology: Thus, we quantified for the first time the serum levels of parent compounds of two bisphenols and four phthalates in patients with MDD. The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP), and di-ethyl-phthalate (DEP), bisphenol A (BPA), and bisphenol S (BPS) in men and women with or without MDD were determined with a gas chromatograph-mass spectrometer. Results/conclusion: We found significant differences between concentrations of BBP between controls and patients with MDD. Interestingly, the serum levels of this compound have a dysmorphic behavior, being much higher in women (~500 ng/mL) than in men (≤10 ng/mL). We did not observe significant changes in the serum concentrations of the other phthalates or bisphenols tested, neither when comparing healthy and sick subjects nor when they were compared by gender. The results point out that BBP has a critical impact on the etiology of MDD disorder in Mexican patients, specifically in women.

186Association between Prenatal Particulate Matter Exposure and Neuropsychiatric Disorders Development.PubMed

Ho Jung Bae, Tamanna Jahan Mony, Se Jin Park
Biomol Ther (Seoul). 2025 Jul 1;33(4):557-571. doi: 10.4062/biomolther.2025.031. Epub 2025 Jun 11.
This comprehensive review explores the relationship between prenatal exposure to particulate matter (PM) air pollution and the development of various neuropsychiatric disorders in offspring. Air pollution, specifically by PM, is a global health concern, with PM and PM being the most detrimental to health. This review delves into the impact of prenatal PM exposure on neurodevelopment and the onset of disorders such as cognitive impairment, Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), anxiety, depression, and schizophrenia. Utilizing data from international databases and focusing on full-text research papers from 2013 to 2023, we identified 18 relevant studies that explore the association between prenatal PM exposure and subsequent neuropsychiatric outcomes. The review discusses the potential mechanisms underlying these associations, including systemic inflammation, oxidative stress, and disruptions in the gut-brain axis. Key findings include the detrimental effects of PM exposure on fetal brain development, leading to cognitive deficits, heightened risk of ASD, ADHD, and altered mental health outcomes. Moreover, the review highlights the need for further research to unravel the complex interplay of genetic, environmental, and individual factors in the development of these disorders. The implications of these findings underscore the importance of reducing air pollution exposure, particularly during pregnancy, to safeguard fetal brain development and prevent neuropsychiatric disorders in offspring.

187Impact of air pollution exposure on the severity of major depressive disorder: Results from the DeprAir study.PubMed

E Borroni, M Buoli, G Nosari, et al.
Eur Psychiatry. 2024 Sep 27;67(1):e61. doi: 10.1192/j.eurpsy.2024.1767.
BACKGROUND: Major depressive disorder (MDD) is one of the most prevalent medical conditions worldwide. Different factors were found to play a role in its etiology, including environmental ones (e.g., air pollution). The aim of this study was to evaluate the association between air pollution exposure and MDD severity. METHODS: Four hundred sixteen MDD subjects were recruited. Severity of MDD and functioning were evaluated through five rating scales: Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAMD), Clinical Global Impression (CGI), Global Assessment of Functioning (GAF), and Sheehan Disability Scale (SDS). Daily mean estimates of particulate matter with diameter ≤10 (PM10) and 2.5 μm (PM2.5), nitrogen dioxide (NO), and apparent temperature (AT) were estimated based on subjects' residential addresses. Daily estimates of the 2 weeks preceding recruitment were averaged to obtain cumulative exposure. Multivariate linear and ordinal regression models were applied to assess the associations between air pollutants and MDD severity, overall and stratifying by hypersusceptibility and AT. RESULTS: Two-thirds of subjects were women and one-third had a family history of depression. Most women had depression with symptoms of anxiety, while men had predominantly melancholic depression. NO exposure was associated with worsening of MDD severity (HAMD: β = 1.94, 95% confidence interval [CI], [0.41-3.47]; GAF: β = -1.93, 95% CI [-3.89 to 0.02]), especially when temperatures were low or among hypersusceptible subjects. PM exposure showed an association with MDD severity only in these subgroups. CONCLUSIONS: Exposure to air pollution worsens MDD severity, with hypersusceptibility and lower temperatures being exacerbating factors.

188Lifestyle medicine for depression.PubMed

Jerome Sarris, Adrienne O'Neil, Carolyn E Coulson, et al.
BMC Psychiatry. 2014 Apr 10;14:107. doi: 10.1186/1471-244X-14-107.
The prevalence of depression appears to have increased over the past three decades. While this may be an artefact of diagnostic practices, it is likely that there are factors about modernity that are contributing to this rise. There is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can potentially be modified, yet they receive little consideration in the contemporary treatment of depression, where medication and psychological intervention remain the first line treatments. "Lifestyle Medicine" provides a nexus between public health promotion and clinical treatments, involving the application of environmental, behavioural, and psychological principles to enhance physical and mental wellbeing. This may also provide opportunities for general health promotion and potential prevention of depression. In this paper we provide a narrative discussion of the major components of Lifestyle Medicine, consisting of the evidence-based adoption of physical activity or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. We also discuss other potential lifestyle factors that have a more nascent evidence base, such as environmental issues (e.g. urbanisation, and exposure to air, water, noise, and chemical pollution), and the increasing human interface with technology. Clinical considerations are also outlined. While data supports that some of these individual elements are modifiers of overall mental health, and in many cases depression, rigorous research needs to address the long-term application of Lifestyle Medicine for depression prevention and management. Critically, studies exploring lifestyle modification involving multiple lifestyle elements are needed. While the judicious use of medication and psychological techniques are still advocated, due to the complexity of human illness/wellbeing, the emerging evidence encourages a more integrative approach for depression, and an acknowledgment that lifestyle modification should be a routine part of treatment and preventative efforts.

189[Postpartum depression and migration].PubMed

Shirin Diop, Luc Turmes, Georg Juckel, et al.
Nervenarzt. 2020 Sep;91(9):822-831. doi: 10.1007/s00115-019-00828-5.
Psychiatric research and care increasingly explore the connection between mental health and migration; however, it is striking that only a small number of analyses exist on the effect of migration on mental ailments specific to women. For example, even though postpartum depression regularly occurs among women with a migration background, in Germany and internationally there is a lack of knowledge on the epidemiology, particularly with respect to factors causing or contributing to postpartum depression among women with a migration background. Prospectively, culturally specific treatment options for women with a migration background are necessary to prevent chronification and subsequent harm to the mother and other family members. With this aim in mind, psychologists, psychiatrists and gynecologists should be aware of the specific factors contributing to the development of postpartum depression among women with a migration background. This overview article focuses on key aspects of postpartum depression, such as epidemiology, symptoms, risk factors and treatment concepts, while contextualizing them with respect to women's experience of migration.

190Depression in older adults.PubMed

Amy Fiske, Julie Loebach Wetherell, Margaret Gatz
Annu Rev Clin Psychol. 2009;5:363-89. doi: 10.1146/annurev.clinpsy.032408.153621.
Depression is less prevalent among older adults than among younger adults, but it can have serious consequences. More than half of cases represent a first onset in later life. Although suicide rates in the elderly are declining, they are still higher than in younger adults and are more closely associated with depression. Depressed older adults are less likely to endorse affective symptoms and more likely to display cognitive changes, somatic symptoms, and loss of interest than are depressed younger adults. Risk factors leading to the development of late-life depression likely comprise complex interactions among genetic vulnerabilities, cognitive diathesis, age-associated neurobiological changes, and stressful events. Insomnia is an often overlooked risk factor for late-life depression. We suggest that a common pathway to depression in older adults, regardless of which predisposing risks are most prominent, may be curtailment of daily activities. Accompanying self-critical thinking may exacerbate and maintain a depressed state. Offsetting the increasing prevalence of certain risk factors in late life are age-related increases in psychological resilience. Other protective factors include higher education and socioeconomic status, engagement in valued activities, and religious or spiritual involvement. Treatments including behavioral therapy, cognitive-behavioral therapy, cognitive bibliotherapy, problem-solving therapy, brief psychodynamic therapy, and life review/reminiscence therapy are effective but are too infrequently used with older adults. Preventive interventions including education for individuals with chronic illness, behavioral activation, cognitive restructuring, problem-solving skills training, group support, and life review have also received support.

191Risk Factors for Depression in Long-Term Care: A Systematic Review.PubMed

Rebecca Chau, David W Kissane, Tanya E Davison
Clin Gerontol. 2019 May-Jun;42(3):224-237. doi: 10.1080/07317115.2018.1490371. Epub 2018 Jul 6.
OBJECTIVES: Depression rates are substantially higher among older adults in long-term care when compared with older adults in the community. Furthermore, the needs of older adults in long-term care are increasingly complex, and risk factors that contribute to depression in this population are unclear. This limits not only the identification of those at risk for depression but also the development of therapeutic interventions. This review summarizes the evidence on risk factors for depression. METHODS: Searches were performed using CINAHL, Cochrane Library, Ovid Medline, PsycINFO and Scopus for research published 1980-2017. Data were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Eleven studies met the inclusion criteria, representing a total of 11,703 participants, with a mean sample size of 1,064. The most consistently supported risk factor was cognitive impairment, followed by functional impairment and baseline depression score. CONCLUSIONS: The studies lacked a systematic approach to investigating risk factors for depression, and the research remains largely atheoretical. Few risk factors were consistently studied, with over 20 risk factors examined no more than once each. Psychological and environmental risk factors, which may be modifiable and have the potential to inform therapeutic interventions and preventative strategies, remain under-studied. CLINICAL IMPLICATIONS: The most consistently supported risk factors-cognitive impairment, functional disability and baseline depression score-have the potential to inform screening protocols and should be monitored longitudinally. When developing psychotherapeutic interventions, close consideration should be given to cognitive and functional impairment as barriers to implementation and uptake.

192[Depression--gender differences].PubMed

Karin Garde
Ugeskr Laeger. 2007 Jun 18;169(25):2422-5.
Unipolar depression is twice as frequent among women in fertile years compared to men. Current biological theories are that stages of life with declining levels of oestrogen could be a trigger of depression. Psychological theories are low self-esteem, sensitivity to lack of social support, comorbidity with anxiety, aggression turned inwards in women, outwards in men, whose comorbidity is alcohol abuse. Social theories are the preponderance of women in poverty and economic dependence. Symptoms and outcome are equal for men and women. Suicide is a greater risk for men, and increases with age; suicide attempts are a greater risk for women, and decline with age. During life span the rates of depression and anxiety and gender differences decline.

193ASSOCIATION BETWEEN SOCIAL MEDIA USE AND DEPRESSION AMONG U.S. YOUNG ADULTS.PubMed

Liu Yi Lin, Jaime E Sidani, Ariel Shensa, et al.
Depress Anxiety. 2016 Apr;33(4):323-31. doi: 10.1002/da.22466. Epub 2016 Jan 19.
BACKGROUND: Social media (SM) use is increasing among U.S. young adults, and its association with mental well-being remains unclear. This study assessed the association between SM use and depression in a nationally representative sample of young adults. METHODS: We surveyed 1,787 adults ages 19 to 32 about SM use and depression. Participants were recruited via random digit dialing and address-based sampling. SM use was assessed by self-reported total time per day spent on SM, visits per week, and a global frequency score based on the Pew Internet Research Questionnaire. Depression was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Scale Short Form. Chi-squared tests and ordered logistic regressions were performed with sample weights. RESULTS: The weighted sample was 50.3% female and 57.5% White. Compared to those in the lowest quartile of total time per day spent on SM, participants in the highest quartile had significantly increased odds of depression (AOR = 1.66, 95% CI = 1.14-2.42) after controlling for all covariates. Compared with those in the lowest quartile, individuals in the highest quartile of SM site visits per week and those with a higher global frequency score had significantly increased odds of depression (AOR = 2.74, 95% CI = 1.86-4.04; AOR = 3.05, 95% CI = 2.03-4.59, respectively). All associations between independent variables and depression had strong, linear, dose-response trends. Results were robust to all sensitivity analyses. CONCLUSIONS: SM use was significantly associated with increased depression. Given the proliferation of SM, identifying the mechanisms and direction of this association is critical for informing interventions that address SM use and depression.

194Associations between rejection sensitivity and mental health outcomes: A meta-analytic review.PubMed

Shuling Gao, Mark Assink, Andrea Cipriani, et al.
Clin Psychol Rev. 2017 Nov;57:59-74. doi: 10.1016/j.cpr.2017.08.007. Epub 2017 Aug 15.
Rejection sensitivity is a personality disposition characterized by oversensitivity to social rejection. Using a three-level meta-analytic model, 75 studies were reviewed that examined associations between rejection sensitivity and five mental health outcomes: depression, anxiety, loneliness, borderline personality disorder, and body dysmorphic disorder. The results showed significant and moderate associations between rejection sensitivity and depression (pooled r=0.332; p<0.001), anxiety (pooled r=0.407; p<0.001), loneliness (pooled r=0.386; p<0.001), borderline personality disorder (pooled r=0.413; p<0.001), and body dysmorphic disorder (pooled r=0.428; p<0.001). The associations between rejection sensitivity and depression, anxiety, and borderline personality disorder varied by type of sample, but the associations were similar for clinical and non-clinical (i.e., community) samples. The association between rejection sensitivity and anxiety was negatively moderated by percentage of females in samples. The association between rejection sensitivity and depression was negatively moderated by length of follow-up. The longitudinal associations between rejection sensitivity and depression, anxiety, and loneliness were stable over time. Implications of the findings for both risk assessment and prevention and intervention strategies in mental health practice are discussed.

195Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases.PubMed

Jose A Santiago, James P Quinn, Judith A Potashkin
Int J Mol Sci. 2023 Mar 21;24(6):5909. doi: 10.3390/ijms24065909.
Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-β, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, , , , , , , and have been identified as genetic risk factors for AD. Likewise, switch genes , , and are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, , , , , , , , , and , overlapped with known genetic variants in depression. Seven switch genes, , , , , , , and were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.

196Clinical guidelines for the use of lifestyle-based mental health care in major depressive disorder: World Federation of Societies for Biological Psychiatry (WFSBP) and Australasian Society of Lifestyle Medicine (ASLM) taskforce.PubMed

Wolfgang Marx, Sam H Manger, Mark Blencowe, et al.
World J Biol Psychiatry. 2023 Jun;24(5):333-386. doi: 10.1080/15622975.2022.2112074. Epub 2022 Oct 6.
OBJECTIVES: The primary objectives of these international guidelines were to provide a global audience of clinicians with (a) a series of evidence-based recommendations for the provision of lifestyle-based mental health care in clinical practice for adults with Major Depressive Disorder (MDD) and (b) a series of implementation considerations that may be applicable across a range of settings. METHODS: Recommendations and associated evidence-based gradings were based on a series of systematic literature searches of published research as well as the clinical expertise of taskforce members. The focus of the guidelines was eight lifestyle domains: physical activity and exercise, smoking cessation, work-directed interventions, mindfulness-based and stress management therapies, diet, sleep, loneliness and social support, and green space interaction. The following electronic bibliographic databases were searched for articles published prior to June 2020: PubMed, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register), CINAHL, PsycINFO. Evidence grading was based on the level of evidence specific to MDD and risk of bias, in accordance with the World Federation of Societies for Biological Psychiatry criteria. RESULTS: Nine recommendations were formed. The recommendations with the highest ratings to improve MDD were the use of physical activity and exercise, relaxation techniques, work-directed interventions, sleep, and mindfulness-based therapies (Grade 2). Interventions related to diet and green space were recommended, but with a lower strength of evidence (Grade 3). Recommendations regarding smoking cessation and loneliness and social support were based on expert opinion. Key implementation considerations included the need for input from allied health professionals and support networks to implement this type of approach, the importance of partnering such recommendations with behaviour change support, and the need to deliver interventions using a biopsychosocial-cultural framework. CONCLUSIONS: Lifestyle-based interventions are recommended as a foundational component of mental health care in clinical practice for adults with Major Depressive Disorder, where other evidence-based therapies can be added or used in combination. The findings and recommendations of these guidelines support the need for further research to address existing gaps in efficacy and implementation research, especially for emerging lifestyle-based approaches (e.g. green space, loneliness and social support interventions) where data are limited. Further work is also needed to develop innovative approaches for delivery and models of care, and to support the training of health professionals regarding lifestyle-based mental health care.

197The associations between screen time and mental health in adolescents: a systematic review.PubMed

Renata Maria Silva Santos, Camila Guimarães Mendes, Guilherme Yanq Sen Bressani, et al.
BMC Psychol. 2023 Apr 20;11(1):127. doi: 10.1186/s40359-023-01166-7.
BACKGROUND: Adolescents have extensive use of screens and, they have common complains related to mental health. Here a systematic review was done to understand the association between screen time and adolescent's mental health. METHOD: This review was conducted in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA. An update search was performed in January 2023 with the following keywords: "screen time," "adolescent," and "mental health" on PubMed, PsycINFO and Scopus databases. RESULTS: 50 articles were included, most have found associations between screen exposure and mental health in adolescents. The most used device by adolescents was the smartphone and the use on weekdays was associated with diminished mental well-being. Social media use was negatively associated with mental well-being and, in girls, associated at higher risk for depression. CONCLUSION: Excessive screen time in adolescents seems associated with mental health problems. Given the profusion and disparity of the results, additional studies are needed to clarify elements such as the screen content or the interaction of adolescents with different screen devices. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022302817.

198#Sleepyteens: Social media use in adolescence is associated with poor sleep quality, anxiety, depression and low self-esteem.PubMed

Heather Cleland Woods, Holly Scott
J Adolesc. 2016 Aug;51:41-9. doi: 10.1016/j.adolescence.2016.05.008. Epub 2016 Jun 10.
This study examined how social media use related to sleep quality, self-esteem, anxiety and depression in 467 Scottish adolescents. We measured overall social media use, nighttime-specific social media use, emotional investment in social media, sleep quality, self-esteem and levels of anxiety and depression. Adolescents who used social media more - both overall and at night - and those who were more emotionally invested in social media experienced poorer sleep quality, lower self-esteem and higher levels of anxiety and depression. Nighttime-specific social media use predicted poorer sleep quality after controlling for anxiety, depression and self-esteem. These findings contribute to the growing body of evidence that social media use is related to various aspects of wellbeing in adolescents. In addition, our results indicate that nighttime-specific social media use and emotional investment in social media are two important factors that merit further investigation in relation to adolescent sleep and wellbeing.

199Screen time and early adolescent mental health, academic, and social outcomes in 9- and 10- year old children: Utilizing the Adolescent Brain Cognitive Development ℠ (ABCD) Study.PubMed

Katie N Paulich, J Megan Ross, Jeffrey M Lessem, et al.
PLoS One. 2021 Sep 8;16(9):e0256591. doi: 10.1371/journal.pone.0256591. eCollection 2021.
In a technology-driven society, screens are being used more than ever. The high rate of electronic media use among children and adolescents begs the question: is screen time harming our youth? The current study draws from a nationwide sample of 11,875 participants in the United States, aged 9 to 10 years, from the Adolescent Brain Cognitive Development Study (ABCD Study®). We investigate relationships between screen time and mental health, behavioral problems, academic performance, sleep habits, and peer relationships by conducting a series of correlation and regression analyses, controlling for SES and race/ethnicity. We find that more screen time is moderately associated with worse mental health, increased behavioral problems, decreased academic performance, and poorer sleep, but heightened quality of peer relationships. However, effect sizes associated with screen time and the various outcomes were modest; SES was more strongly associated with each outcome measure. Our analyses do not establish causality and the small effect sizes observed suggest that increased screen time is unlikely to be directly harmful to 9-and-10-year-old children.

200Adverse physiological and psychological effects of screen time on children and adolescents: Literature review and case study.PubMed

Gadi Lissak
Environ Res. 2018 Jul;164:149-157. doi: 10.1016/j.envres.2018.01.015. Epub 2018 Feb 27.
UNLABELLED: A growing body of literature is associating excessive and addictive use of digital media with physical, psychological, social and neurological adverse consequences. Research is focusing more on mobile devices use, and studies suggest that duration, content, after-dark-use, media type and the number of devices are key components determining screen time effects. Physical health effects: excessive screen time is associated with poor sleep and risk factors for cardiovascular diseases such as high blood pressure, obesity, low HDL cholesterol, poor stress regulation (high sympathetic arousal and cortisol dysregulation), and Insulin Resistance. Other physical health consequences include impaired vision and reduced bone density. Psychological effects: internalizing and externalizing behavior is related to poor sleep. Depressive symptoms and suicidal are associated to screen time induced poor sleep, digital device night use, and mobile phone dependency. ADHD-related behavior was linked to sleep problems, overall screen time, and violent and fast-paced content which activates dopamine and the reward pathways. Early and prolonged exposure to violent content is also linked to risk for antisocial behavior and decreased prosocial behavior. Psychoneurological effects: addictive screen time use decreases social coping and involves craving behavior which resembles substance dependence behavior. Brain structural changes related to cognitive control and emotional regulation are associated with digital media addictive behavior. A case study of a treatment of an ADHD diagnosed 9-year-old boy suggests screen time induced ADHD-related behavior could be inaccurately diagnosed as ADHD. Screen time reduction is effective in decreasing ADHD-related behavior. CONCLUSIONS: Components crucial for psychophysiological resilience are none-wandering mind (typical of ADHD-related behavior), good social coping and attachment, and good physical health. Excessive digital media use by children and adolescents appears as a major factor which may hamper the formation of sound psychophysiological resilience.

201The relationship between addictive use of social media and video games and symptoms of psychiatric disorders: A large-scale cross-sectional study.PubMed

Cecilie Schou Andreassen, Joël Billieux, Mark D Griffiths, et al.
Psychol Addict Behav. 2016 Mar;30(2):252-62. doi: 10.1037/adb0000160.
Over the last decade, research into "addictive technological behaviors" has substantially increased. Research has also demonstrated strong associations between addictive use of technology and comorbid psychiatric disorders. In the present study, 23,533 adults (mean age 35.8 years, ranging from 16 to 88 years) participated in an online cross-sectional survey examining whether demographic variables, symptoms of attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, and depression could explain variance in addictive use (i.e., compulsive and excessive use associated with negative outcomes) of two types of modern online technologies: social media and video games. Correlations between symptoms of addictive technology use and mental disorder symptoms were all positive and significant, including the weak interrelationship between the two addictive technological behaviors. Age appeared to be inversely related to the addictive use of these technologies. Being male was significantly associated with addictive use of video games, whereas being female was significantly associated with addictive use of social media. Being single was positively related to both addictive social networking and video gaming. Hierarchical regression analyses showed that demographic factors explained between 11 and 12% of the variance in addictive technology use. The mental health variables explained between 7 and 15% of the variance. The study significantly adds to our understanding of mental health symptoms and their role in addictive use of modern technology, and suggests that the concept of Internet use disorder (i.e., "Internet addiction") as a unified construct is not warranted.

202Health Literacy Promotion and Digital Interventions for Depressive Disorders.PubMed

Jacqueline Posselt, Jonas Lander, Marie-Luise Dierks
Health Lit Res Pract. 2024 Oct;8(4):e236-e245. doi: 10.3928/24748307-20240730-01. Epub 2024 Dec 6.
BACKGROUND: The lack of therapeutic treatment options for depressive disorders increases the relevance of digital interventions for patients and general practitioners (GPs), particularly to bridge waiting times. However, patients may require adequate (digital) health literacy (HL) to partake in such interventions. OBJECTIVE: This study contrasts expected benefits and risks of digital mental health interventions, specifically digital therapeutics on prescription (DTx), among GPs and patients with depression according to HL dimensions (access, understanding, appraisal, and application) and patients' personal determinants. METHODS: We conducted semi-structured interviews with purposively sampled GPs ( = 17) and patients with mild or moderate depression ( = 17) in Germany. The interviews were audio-recorded, transcribed verbatim, and coded. Data were analyzed using qualitative content analysis. KEY RESULTS: DTx include benefits to access health information and promote HL as DTx can improve understanding of health content and foster self-management skills. But DTx also implies risks for routine care distribution and creates new media barriers. During waiting times patients appraise DTx for themselves as more positive than GPs expect. However, digital- and disease-specific challenges such as non-commitment, listlessness or lethargy appear to hinder the use of DTx in practical situations. While GPs were not convinced about the digital skills of their patients, patients raised concerns that depressive symptoms may inhibit them from actual use. CONCLUSION: In the context of DTx for depressive disorders, patients' mental health needs are seldom noticed and rarely promoted. To foster (digital) HL, DTx should be comprehensively embedded in supply situations. [].

203Are digital psychological interventions for psychological distress and quality of life in cancer patients effective? A systematic review and network meta-analysis.PubMed

Tao Zhang, Zhihong Ren, Claire Elizabeth Wakefield, et al.
Clin Psychol Rev. 2025 Feb;115:102520. doi: 10.1016/j.cpr.2024.102520. Epub 2024 Nov 26.
BACKGROUND: Many cancer patients experience psychological distress and/or poor quality of life during or after their cancer treatment, yet they face multiple barriers to accessing psychological support. Digital psychological interventions represent a promising approach for addressing these barriers, however their comparative effectiveness remains uncertain. METHODS: Nine databases were searched for randomized controlled trials (RCTs) from inception to July 2024. The primary outcomes were psychological distress and quality of life, and the secondary outcomes were measures of depression, anxiety, insomnia, fatigue, and fear of cancer recurrence in this study. RESULTS: One hundred and thirty-six RCTs with 23,154 participants were identified. Of these interventions, three types-digitally-delivered cognitive behavioral therapy (CBT), health education, and virtual reality therapy (VRT)-demonstrated significant reductions in psychological distress compared to non-active controls. Digital CBT, narrative interventions, and VRT significantly improved quality of life compared to non-active controls. For depression, both digital CBT and VRT were superior to the non-active control group. Regarding anxiety, CBT, psychoeducation, and VRT outperformed the non-active control group. In terms of fatigue, CBT, psychoeducation, VRT, and multi-component interventions all showed enhanced efficacy compared to the non-active control group. However, only CBT exhibited significantly superior effectiveness in alleviating insomnia compared to non-active controls. Similarly, only mindfulness-based interventions significantly reduced fear of cancer recurrence compared to the non-active control condition. CONCLUSIONS: Our results suggest that digital CBT and VRT are highly promising options for reducing psychological distress and enhancing the quality of life among cancer patients; further high-quality randomized controlled trials involving diverse populations are essential to validate these findings.

204Acceptability of Digital Mental Health Interventions for Depression and Anxiety: Systematic Review.PubMed

Carrie K Y Lau, Anthony Saad, Bettina Camara, et al.
J Med Internet Res. 2024 Oct 28;26:e52609. doi: 10.2196/52609.
BACKGROUND: Depression and anxiety disorders are common, and treatment often includes psychological interventions. Digital health interventions, delivered through technologies such as web-based programs and mobile apps, are increasingly used in mental health treatment. Acceptability, the extent to which an intervention is viewed positively, has been identified as contributing to patient adherence and engagement with digital health interventions. Acceptability, therefore, impacts the benefit derived from using digital health interventions in treatment. Understanding the acceptability of digital mental health interventions among patients with depression or anxiety disorders is essential to maximize the effectiveness of their treatment. OBJECTIVE: This review investigated the acceptability of technology-based interventions among patients with depression or anxiety disorders. METHODS: A systematic review was performed based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and PROSPERO (International Prospective Register of Systematic Reviews) guidelines. We searched PubMed, Web of Science, and Ovid in May 2022. Studies were included if they evaluated digital interventions for the treatment of depression or anxiety disorders and investigated their acceptability among adult patients. Studies were excluded if they targeted only specific populations (eg, those with specific physical health conditions), investigated acceptability in healthy individuals or patients under the age of 18 years, involved no direct interaction between patients and technologies, used technology only as a platform for traditional care (eg, videoconferencing), had patients using technologies only in clinical or laboratory settings, or involved virtual reality technologies. Acceptability outcome data were narratively synthesized by the direction of acceptability using vote counting. Included studies were evaluated using levels of evidence from the Oxford Centre for Evidence-Based Medicine. The risk of bias was assessed using a tool designed for this review and GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). RESULTS: A total of 143 articles met the inclusion criteria, comprising 67 (47%) articles on interventions for depression, 65 (45%) articles on interventions for anxiety disorders, and 11 (8%) articles on interventions for both. Overall, 90 (63%) were randomized controlled trials, 50 (35%) were other quantitative studies, and 3 (2%) were qualitative studies. Interventions used web-based programs, mobile apps, and computer programs. Cognitive behavioral therapy was the basis of 71% (102/143) of the interventions. Digital mental health interventions were generally acceptable among patients with depression or anxiety disorders, with 88% (126/143) indicating positive acceptability, 8% (11/143) mixed results, and 4% (6/143) insufficient information to categorize the direction of acceptability. The available research evidence was of moderate quality. CONCLUSIONS: Digital mental health interventions seem to be acceptable to patients with depression or anxiety disorders. Consistent use of validated measures for acceptability would enhance the quality of evidence. Careful design of acceptability as an evaluation outcome can further improve the quality of evidence and reduce the risk of bias. TRIAL REGISTRATION: Open Science Framework Y7MJ4; https://doi.org/10.17605/OSF.IO/SPR8M.

205The effect of digital health interventions on postpartum depression or anxiety: a systematic review and meta-analysis of randomized controlled trials.PubMed

Adam K Lewkowitz, Anna R Whelan, Nina K Ayala, et al.
Am J Obstet Gynecol. 2024 Jan;230(1):12-43. doi: 10.1016/j.ajog.2023.06.028. Epub 2023 Jun 15.
OBJECTIVE: This study aimed to examine the effect of digital health interventions compared with treatment as usual on preventing and treating postpartum depression and postpartum anxiety. DATA SOURCES: Searches were conducted in Ovid MEDLINE, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. STUDY ELIGIBILITY REQUIREMENTS: The systematic review included full-text randomized controlled trials comparing digital health interventions with treatment as usual for preventing or treating postpartum depression and postpartum anxiety. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors independently screened all abstracts for eligibility and independently reviewed all potentially eligible full-text articles for inclusion. A third author screened abstracts and full-text articles as needed to determine eligibility in cases of discrepancy. The primary outcome was the score on the first ascertainment of postpartum depression or postpartum anxiety symptoms after the intervention. Secondary outcomes included screening positive for postpartum depression or postpartum anxiety --as defined in the primary study --and loss to follow-up, defined as the proportion of participants who completed the final study assessment compared with the number of initially randomized participants. For continuous outcomes, the Hedges method was used to obtain standardized mean differences when the studies used different psychometric scales, and weighted mean differences were calculated when studies used the same psychometric scales. For categorical outcomes, pooled relative risks were estimated. RESULTS: Of 921 studies originally identified, 31 randomized controlled trials-corresponding to 5532 participants randomized to digital health intervention and 5492 participants randomized to treatment as usual-were included. Compared with treatment as usual, digital health interventions significantly reduced mean scores ascertaining postpartum depression symptoms (29 studies: standardized mean difference, -0.64 [95% confidence interval, -0.88 to -0.40]; I=94.4%) and postpartum anxiety symptoms (17 studies: standardized mean difference, -0.49 [95% confidence interval, -0.72 to -0.25]; I=84.6%). In the few studies that assessed screen-positive rates for postpartum depression (n=4) or postpartum anxiety (n=1), there were no significant differences between those randomized to digital health intervention and treatment as usual. Overall, those randomized to digital health intervention had 38% increased risk of not completing the final study assessment compared with those randomized to treatment as usual (pooled relative risk, 1.38 [95% confidence interval, 1.18-1.62]), but those randomized to app-based digital health intervention had similar loss-to-follow-up rates as those randomized to treatment as usual (relative risk, 1.04 [95% confidence interval, 0.91-1.19]). CONCLUSION: Digital health interventions modestly, but significantly, reduced scores assessing postpartum depression and postpartum anxiety symptoms. More research is needed to identify digital health interventions that effectively prevent or treat postpartum depression and postpartum anxiety but encourage ongoing engagement throughout the study period.