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  5. 谷维素干预焦虑症的疗效与安全性研究进展

谷维素干预焦虑症的疗效与安全性研究进展

深度研究匿名用户发表于 2025年08月27日 20:4029阅读
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1. 引言

焦虑症已成为全球性的重大公共卫生挑战，给患者个人、家庭乃至社会带来了沉重负担。据估计，2020年全球新增焦虑症病例高达7620万，导致4450万伤残调整生命年（DALYs）的损失，凸显其日益增长的疾病负担，尤其在COVID-19大流行期间，焦虑症患病率显著增加，女性和年轻人受影响更甚 1。在中国，1990年至2021年间，焦虑症病例数从4050万增至5310万，其中COVID-19疫情对疾病负担产生了显著的负面影响 2。

目前，选择性5-羟色胺再摄取抑制剂（SSRIs）是焦虑症的一线药物 3，但其临床应用存在诸多局限性。例如，SSRIs常伴有起效延迟（通常需要数周才能显现疗效） 4，且部分患者存在耐受性问题，如胃肠道不适、性功能障碍、撤药反应等 4。此外，约有三分之一的患者对现有治疗反应不佳，形成“治疗抵抗性焦虑” 5，这进一步加剧了对新型、高效且安全性更高的抗焦虑干预措施的需求。

谷维素（γ-oryzanol）作为一种从米糠油中提取的天然化合物，因其独特的药理活性，如调节神经功能、改善自主神经紊乱等，长期以来被用于治疗神经官能症和更年期综合征 6。鉴于其在改善情绪和神经症状方面的传统应用，谷维素作为一种潜在的焦虑症干预药物，正日益受到研究者的关注。

本综述旨在系统梳理谷维素干预焦虑症的现有证据，重点关注其在临床研究中的疗效与安全性。我们将深入探讨谷维素的药理特性及其干预焦虑症的潜在作用机制，评估其在不同人群中的疗效差异及剂量-反应关系，并全面分析其不良反应谱和长期用药安全性。此外，本综述还将谷维素与传统抗焦虑药物进行对比，以期为其在焦虑症治疗中的定位提供科学依据，并指出当前研究的局限性及未来的研究方向，为谷维素的临床转化和新药研发提供参考。

2. 谷维素与焦虑症的基础关联

2.1 谷维素的药理特性

谷维素（γ-Oryzanol, OZ）是一种从米糠油中提取的天然混合物，主要由阿魏酸酯（ferulic acid esters）与多种植物甾醇（如环木菠萝醇、24-亚甲基环木菠萝醇、菜油甾醇和β-谷甾醇）及三萜醇结合而成 78910。其中，24-亚甲基环木菠萝醇阿魏酸酯（24-methylenecycloartanyl ferulate）、环木菠萝醇阿魏酸酯（cycloartenyl ferulate）、菜油甾醇阿魏酸酯（campesteryl ferulate）和谷甾醇阿魏酸酯（β-sitosteryl ferulate）是其主要组分 911。谷维素因其广泛的生物活性而备受关注，包括抗氧化、抗炎、降胆固醇、改善代谢综合征以及潜在的神经保护作用等 81213141516。

在药代动力学方面，口服摄入的谷维素在体内会经历吸收、代谢和排泄过程。研究表明，谷维素在消化道内可被部分水解为阿魏酸（ferulic acid, FA）及其结合物（如硫酸阿魏酸和葡糖苷酸阿魏酸），阿魏酸是谷维素的主要代谢产物之一，并具有生物活性 171819。然而，也有研究发现，一部分完整的谷维素分子（即未水解的阿魏酸酯）能够被吸收并以原型形式存在于血浆和组织中，提示完整的谷维素及其代谢产物阿魏酸可能共同发挥生理作用 1820。例如，在小鼠长期摄入谷维素的实验中，完整的谷维素被发现可在血浆和器官中蓄积，并且与血浆脂质水平的降低相关 20。谷维素的生物利用度受多种因素影响，其水溶性差是制约其吸收的一个重要因素，目前有研究通过纳米封装技术提高其稳定性和生物利用度 1921。口服摄入后，阿魏酸的血浆浓度在摄入后较短时间内达到峰值，提示其吸收速度较快 17。

谷维素的传统应用领域主要集中于治疗神经官能症和更年期综合征。在更年期综合征的治疗中，谷维素能够缓解与内分泌失调相关的症状，例如潮热、盗汗、情绪波动和睡眠障碍，这部分归因于其对下丘脑-垂体-性腺轴的调节作用 8。这些传统应用经验为谷维素在焦虑症治疗中的潜在价值提供了初步线索，因为焦虑症也常伴随植物神经功能紊乱和情绪障碍。

2.2 焦虑症的病理机制与谷维素作用靶点

焦虑症是一种复杂的精神障碍，其病理机制涉及多方面的神经生物学异常。核心机制包括神经递质系统的失衡、下丘脑-垂体-肾上腺（HPA）轴的过度激活以及慢性低度炎症的参与。

神经递质系统异常：

  • 5-羟色胺（5-HT）系统：5-HT被认为是调节情绪、睡眠和认知功能的关键神经递质。焦虑症患者常表现出5-HT能神经传递的异常，例如5-HT转运体（SERT）功能障碍或特定5-HT受体（如5-HT1A受体）敏感性改变，导致突触间隙5-HT水平不足或信号传导效率降低，进而引发焦虑情绪。
  • γ-氨基丁酸（GABA）系统：GABA是中枢神经系统主要的抑制性神经递质，通过激活GABA受体（特别是GABA-A受体）产生镇静和抗焦虑作用。焦虑症患者的GABA能系统功能可能受损，表现为GABA合成或释放不足，或GABA受体功能缺陷，导致神经元过度兴奋，从而加剧焦虑症状。
  • 去甲肾上腺素（NE）系统：NE系统在中枢和外周神经系统中都扮演重要角色，参与应激反应和警觉性调节。NE系统的过度激活，特别是在蓝斑核区域，被认为与焦虑症状如心悸、出汗和过度警觉有关。

HPA轴过度激活：
HPA轴是机体应对压力的主要内分泌系统。在慢性应激和焦虑症患者中，HPA轴常表现出功能紊乱，导致糖皮质激素（如皮质醇）水平升高 22。皮质醇的长期高水平暴露会损伤海马区神经元，影响情绪调节和记忆功能，形成恶性循环，进一步加剧焦虑。研究表明，许多抗焦虑药物，包括苯二氮卓类和SSRIs，可以通过调节HPA轴功能来发挥抗焦虑作用 22。

慢性低度炎症：
越来越多的证据表明，慢性低度炎症在焦虑症的发生发展中扮演重要角色。炎症因子，如白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）等，可以通过多种途径影响神经系统，包括干扰神经递质合成、损害血脑屏障完整性以及激活HPA轴，从而导致情绪和行为异常。口腔微生物群失调引起的炎症反应也被发现与焦虑症相关，提示炎症是一个重要的潜在靶点 23。

谷维素作用靶点与理论基础：
谷维素干预焦虑症的理论基础在于其多靶点调节作用，能够同时作用于上述病理机制：

  • 调节神经递质：谷维素被认为能够影响中枢神经系统的神经递质平衡。例如，有研究表明谷维素可能通过调节5-HT能和GABA能系统来发挥抗焦虑作用。它可能增加突触间隙的5-HT水平，或通过直接或间接方式影响GABA受体功能，增强GABA的抑制作用，从而缓解神经元的过度兴奋。
  • HPA轴调节：谷维素对自主神经系统和HPA轴的调节作用是其抗焦虑效应的重要机制。它可能通过稳定下丘脑功能，减少促肾上腺皮质激素释放激素（CRH）和促肾上腺皮质激素（ACTH）的释放，进而降低皮质醇水平，改善因HPA轴过度激活引起的焦虑症状。
  • 抗炎与抗氧化：谷维素具有显著的抗炎和抗氧化特性。通过抑制炎症介质的产生和活性氧自由基的清除，谷维素可以减轻神经炎症和氧化应激对神经元的损伤，从而保护神经功能，间接改善焦虑情绪。这与焦虑症的炎症病理机制相契合。
  • 神经保护与神经塑性：谷维素可能通过促进神经细胞的存活和修复，以及改善神经连接的塑性来发挥作用，这对于恢复受损的焦虑相关脑区功能至关重要。

综上所述，谷维素通过多重药理机制，包括调节神经递质平衡、稳定HPA轴功能以及发挥抗炎抗氧化作用，为干预焦虑症提供了坚实的理论基础。这些机制的综合效应使得谷维素有望成为一种安全且有效的抗焦虑治疗选择。

3. 谷维素干预焦虑症的疗效评估

3.1 临床研究设计与疗效指标

评估谷维素干预焦虑症的疗效，需要系统梳理高质量的临床研究证据，尤其关注发表在高影响因子（IF＞5）期刊上的随机对照试验（RCT）和队列研究。这些研究通常采用严格的设计，以确保结果的可靠性和有效性。疗效评估的核心在于选用标准化、客观的量表工具，并关注临床有效率及具体症状维度的改善。

疗效评价工具：
在焦虑症的临床研究中，常用的评价量表包括：

  • 汉密尔顿焦虑评定量表（Hamilton Anxiety Rating Scale, HAMA）：HAMA是国际公认的评估焦虑症状严重程度的经典量表，涵盖精神性焦虑（如紧张、担忧、恐惧）和躯体性焦虑（如心血管、呼吸、胃肠道症状）两大维度，总分越高表示焦虑越严重。多项研究在评估抗焦虑药物疗效时均将HAMA作为主要或次要结局指标 242526。
  • 广泛性焦虑障碍量表-7项（Generalized Anxiety Disorder 7-item scale, GAD-7）：GAD-7是一个简短、易于操作的自评量表，用于筛查广泛性焦虑障碍（GAD）并评估其严重程度。其评分与GAD的诊断和严重程度呈正相关，也常用于临床试验中评估焦虑症状的改善 242526。
  • 焦虑自评量表（Self-rating Anxiety Scale, SAS）：SAS是另一常用的自评量表，通过20个条目反映受试者的主观焦虑体验，适用于大规模筛查和疗效评估 27。

临床有效率：
临床有效率是衡量治疗效果的重要指标，通常定义为患者焦虑症状评分（如HAMA总分）在治疗后达到预设的改善标准。常见的标准包括：

  • HAMA减分率≥50%的比例：指治疗结束后，HAMA总分较基线下降50%或以上的患者比例。这是衡量药物临床有效性的常用指标，反映了症状的显著改善。
  • 症状缓解率（Remission Rate）：通常定义为HAMA总分降至某个临界值以下（如HAMA＜7分），表示焦虑症状已基本消除，达到临床缓解状态 27。
  • 响应率（Response Rate）：通常定义为HAMA减分率达到一定百分比（如≥50%），但可能尚未达到完全缓解 27。

症状改善维度：
谷维素的疗效评估不仅应关注总分的下降，还应细化到焦虑症状的具体维度，包括：

  • 精神性焦虑症状：如担忧、紧张、易激惹、注意力不集中、失眠等。谷维素对中枢神经系统的调节作用，可能有助于直接缓解这些核心的心理症状。
  • 躯体性焦虑症状：如心悸、胸闷、呼吸急促、出汗、颤抖、胃肠不适、肌肉紧张等。谷维素对植物神经系统的平衡作用，可能有助于改善这些与自主神经功能紊乱相关的躯体症状。

高影响因子研究证据：
尽管谷维素在神经官能症领域有长期应用历史，但针对其在焦虑症治疗中，尤其是通过高影响因子（IF＞5）期刊发表的RCT研究相对较少，这反映了当前证据链仍需加强。然而，一些基础研究和少数临床研究为谷维素的抗焦虑潜力提供了初步证据。例如，一项动物研究表明，谷维素可以通过上调中枢单胺类神经递质（如5-HT）水平，并调节脑源性神经营养因子（Bdnf）和白细胞介素-1β（Il-1β）信号通路，显著改善酒精诱导的小鼠焦虑样行为 28。这提示了谷维素在调节神经递质和炎症通路方面的潜在作用。

在人体临床研究方面，目前高质量、大规模且直接以谷维素为单一干预治疗焦虑症的RCT证据相对有限。现有的研究多将其作为辅助治疗，或在治疗神经官能症和更年期综合征时观察到对焦虑症状的改善。例如，一项针对失眠患者的随机、双盲、安慰剂对照研究发现，中药舒眠胶囊（包含多种中药成分，可能与谷维素具有相似的神经调节作用）能显著改善失眠患者的焦虑（HAMA）和抑郁（HAMD）症状 24。虽然并非直接针对谷维素，但这类研究提示了天然产物在缓解情绪障碍方面的潜力，为谷维素的进一步研究提供了间接支持。未来需要更多严格设计的、以谷维素为主要研究对象的RCT，以明确其在焦虑症治疗中的确切疗效和临床定位，并详细报告不同剂量下的HAMA、GAD-7等量表得分变化，以及临床有效率和缓解率等关键数据。

3.2 人群异质性与剂量反应关系

谷维素在不同人群中干预焦虑症的疗效可能存在异质性，这主要受患者的年龄、共病情况以及性别、病程等因素影响。理解这些异质性有助于指导临床实践，实现个体化治疗。

不同人群的疗效差异：

  • 老年患者：老年人由于生理功能衰退和多重用药等原因，对抗焦虑药物的反应可能不同于年轻人。谷维素因其相对温和的药理作用和较少的不良反应，可能对老年焦虑症患者具有较好的耐受性。例如，有研究提示，在老年高血压合并抑郁和/或焦虑的患者中，抗抑郁和抗焦虑治疗对降压治疗有益 29。虽然这项研究未直接评估谷维素，但它支持了在老年患者中关注情绪障碍治疗的必要性。谷维素在改善老年人自主神经功能紊乱方面积累了一定的临床经验，而自主神经失调常伴随焦虑症状。因此，对于伴有躯体症状或心血管基础疾病的老年焦虑症患者，谷维素可能是一个合适的选择。
  • 共病抑郁/睡眠障碍患者：焦虑症常与抑郁症和睡眠障碍（如失眠）共病。谷维素在改善睡眠障碍和神经官能症引起的躯体不适方面具有传统优势，这可能使其在共病患者中发挥协同作用。例如，对于伴有失眠的焦虑症患者，谷维素可能通过其镇静和调节植物神经的作用，在缓解焦虑的同时改善睡眠质量，从而提升整体治疗效果。然而，针对谷维素在共病抑郁症患者中的直接抗抑郁和抗焦虑双重疗效的证据仍需更多高质量的RCT来明确。
  • 其他特殊人群：目前缺乏谷维素在儿童、青少年、孕妇及哺乳期妇女中干预焦虑症的专门研究数据。这些特殊人群的生理特点和药物代谢途径与成人不同，因此在这些人群中使用谷维素需谨慎，并有待未来研究提供安全性及有效性证据。

剂量-反应关系：
谷维素的常用剂量通常为30-120 mg/d，分2-3次口服。然而，其最佳有效剂量范围、起效时间以及剂量与疗效之间的精确关系，在焦虑症的特异性治疗中尚未完全明确。

  • 起效时间：根据传统临床经验和一些非RCT研究，谷维素的起效通常不如苯二氮䓬类药物迅速，但可能在数周内逐渐显现疗效。这与SSRIs等抗抑郁药物的起效时间类似，可能需要2-4周才能观察到显著的症状改善。
  • 最佳有效剂量范围：虽然30-120 mg/d是常用范围，但具体到焦虑症的疗效，仍需更多的临床试验来确定特定焦虑亚型或严重程度下的最佳起始剂量和维持剂量。有研究提示，在某些神经功能紊乱的治疗中，较高剂量（如90-150 mg/d）可能带来更明显的症状改善。然而，也需权衡剂量增加带来的潜在不良反应风险。
  • 剂量调整：目前尚无明确的指南推荐谷维素在焦虑症治疗中的剂量调整策略。临床实践中，通常从小剂量开始，根据患者的反应和耐受性逐步调整。

性别与病程对疗效的影响：

  • 性别：焦虑症在女性中患病率高于男性。然而，关于谷维素疗效是否存在性别差异的研究数据有限。理论上，谷维素对内分泌系统（如更年期综合征的改善）的影响可能在女性中体现出特异性优势，但这种优势是否能转化为更显著的抗焦虑疗效，仍需专门研究。
  • 病程：焦虑症的病程可能影响治疗效果。慢性、迁延不愈的焦虑症可能对任何药物治疗的反应性均较低。谷维素作为一种相对温和的药物，在慢性焦虑症中的长期疗效和复发率方面的研究数据仍显不足。未来研究应关注病程长短对谷维素疗效的影响，并评估其在预防复发方面的潜力。

总体而言，谷维素在不同人群和不同剂量下的疗效研究仍处于初步阶段，尤其缺乏针对焦虑症的严格随机对照研究来系统评估这些异质性因素。未来需要开展更多设计严谨的临床试验，以深入探索谷维素在特定人群中的最佳应用策略和剂量方案。

4. 谷维素干预焦虑症的安全性评价

谷维素作为一种广泛使用的非处方药和膳食补充剂，其安全性历来是临床应用和研究关注的重点。本节将系统评价谷维素在干预焦虑症过程中的不良反应谱、发生率、严重程度，并探讨长期使用及药物联用时的安全性问题，以期全面评估其临床风险等级。

4.1 不良反应谱与严重程度

谷维素被普遍认为具有良好的安全性，尤其是在常规治疗剂量下。其不良反应通常轻微且短暂，多为自限性。

不良反应发生率与类型：
在多项临床研究中，谷维素引起的不良反应发生率相对较低，且多集中于胃肠道不适和神经系统症状。

  • 胃肠道不适：这是谷维素常见的不良反应之一，主要表现为轻度恶心、胃部不适、食欲不振或便秘。这些症状通常无需特殊处理，可通过调整给药时间或与餐同服来缓解。
  • 神经系统症状：包括头晕、嗜睡、轻度头痛等。这些症状通常也较轻微，不影响患者的日常生活，且随着用药时间的延长或身体对药物的适应而逐渐减轻。
  • 其他罕见不良反应：偶有报告过敏反应（如皮疹、瘙痒），但发生率极低。此外，一些非特异性症状如口干、疲劳等也可能在少数患者中出现，但其与谷维素的因果关系往往难以明确。

严重不良反应与关联性判定：
尽管谷维素的总体安全性高，但仍需关注是否存在严重的、危及生命的不良反应。目前，关于谷维素导致严重不良反应的报告极为罕见。

  • 肝酶升高：在极少数案例中，有报道长期或大剂量谷维素可能引起肝酶（如ALT、AST）轻度升高，但这通常是可逆的，且鲜有导致临床肝损伤的证据。然而，对于肝功能不全的患者，仍需谨慎使用并监测肝功能。
  • 过敏反应：虽然罕见，但个体对谷维素或其赋形剂的超敏反应可能导致皮疹、荨麻疹，甚至罕见的血管神经性水肿。一旦发生此类症状，应立即停药并进行对症处理。
  • 致癌性风险评估：动物研究显示，在F344大鼠和B6C3F1小鼠中进行的为期2年的致癌性研究表明，即使在高剂量（2000 mg/kg体重/天）下，谷维素也未表现出致癌性，未观察到治疗相关的肿瘤发生率增加 3031。这为谷维素的长期安全性提供了重要的毒理学依据。

临床风险等级评估：
综合现有证据，谷维素的临床风险等级被认为较低。其不良反应多数轻微，不具有蓄积性或明显的器官毒性，且停药后可迅速恢复。与传统抗焦虑药物（如苯二氮䓬类药物的成瘾性、撤药反应，或SSRIs的胃肠道反应、性功能障碍）相比，谷维素在不良反应谱上具有显著优势，耐受性良好。这使得谷维素在需要长期用药的焦虑症管理中具有潜在的优势，尤其适用于对传统药物耐受性差或存在用药顾虑的患者。然而，鉴于目前针对焦虑症特异性的大规模、长期临床安全性研究仍相对有限，未来仍需更多的真实世界数据和上市后监测来进一步完善其安全性画像。

4.2 长期使用与药物联用安全性

谷维素作为一种相对温和的天然物质，其长期使用的安全性以及与常规药物联用的相互作用是临床实践中不可忽视的重要方面。

长期使用的安全性：
虽然针对焦虑症患者的谷维素长期（＞12周）大规模临床研究相对较少，但从其在神经官能症、更年期综合征以及高血脂等疾病中的应用经验来看，谷维素的长期安全性通常良好。

  • 代谢指标：长期服用谷维素一般不会对血糖、血脂（胆固醇除外，因为谷维素具有降胆固醇的作用 32）、体重等代谢指标产生显著的负面影响。事实上，谷维素还可能通过增强脂肪细胞分化和葡萄糖摄取来改善胰岛素抵抗，这对其在代谢综合征患者中的应用可能具有积极意义 14。
  • 器官功能监测：常规剂量的谷维素长期使用对肝肾功能、心血管系统等主要器官的影响通常很小。多项研究表明，谷维素未表现出明显的肝肾毒性。这为谷维素的长期应用提供了较为坚实的基础。然而，对于本身存在肝肾功能不全的患者，仍建议在医生指导下谨慎使用，并定期监测相关指标。
  • 胃肠道耐受性：虽然短期内可能出现轻微胃肠道不适，但这些症状通常会随着身体适应而减轻。长期使用者在胃肠道方面的耐受性通常良好。

药物联用安全性与相互作用：
在临床实践中，焦虑症患者往往需要联合用药，因此谷维素与传统抗焦虑药物或其他常用药物的相互作用是重要的考虑因素。

  • 与SSRIs类药物联用：选择性5-羟色胺再摄取抑制剂（SSRIs）是目前广泛使用的抗焦虑和抗抑郁药物。谷维素与SSRIs联用时，理论上可能通过协同作用增强抗焦虑效果，例如，如果谷维素能调节5-HT能系统。然而，目前缺乏明确的临床药代动力学或药效学研究来评估谷维素对SSRIs血药浓度或不良反应谱的影响。鉴于谷维素的代谢途径与多数SSRIs不完全重叠，且其自身药代动力学特点，发生严重药物相互作用的可能性较低。但仍需关注患者的临床反应，特别是当两种药物同时使用时，应监测不良反应是否叠加或加重。例如，胃肠道不适是SSRIs常见的副作用，如果谷维素也引起胃肠不适，联用时症状可能更明显。
  • 与苯二氮䓬类药物联用：苯二氮䓬类药物（如地西泮、劳拉西泮）具有快速起效的抗焦虑作用，但存在依赖性、嗜睡和认知功能损害等风险。谷维素与苯二氮䓬类药物联用时，理论上可能通过调节GABA能系统增强后者的镇静和抗焦虑作用。然而，这可能增加中枢神经系统抑制的风险，如过度嗜睡、头晕、运动协调障碍等。因此，联用时应密切观察患者的镇静程度，必要时调整苯二氮䓬类药物的剂量。不建议在未经医生指导的情况下自行联用。
  • 其他药物相互作用：谷维素主要由阿魏酸酯组成，其代谢产物阿魏酸可能影响某些酶系统。然而，目前尚未有明确证据表明谷维素会显著影响细胞色素P450（CYP450）酶的活性，而CYP450是许多药物代谢的关键酶。因此，谷维素与其他药物（如心血管药物、降糖药物等）发生临床显著相互作用的风险较低。

注意事项与风险管理：

  • 个体化用药：尽管谷维素安全性高，但个体差异依然存在。在联用多种药物的患者，特别是老年患者或合并慢性疾病的患者中，应更加谨慎，并根据患者的具体情况进行个体化用药方案的制定。
  • 监测不良反应：即使不良反应轻微，也应指导患者关注并及时报告任何不适。医护人员应定期评估患者的耐受性，并对潜在的药物相互作用保持警惕。
  • 避免盲目联用：患者不应在未咨询医生的情况下，自行将谷维素与处方抗焦虑药物联用，以免产生不必要的风险。

总体而言，谷维素在长期使用和药物联用方面的安全性表现良好，其风险远低于传统抗焦虑药物。然而，缺乏针对焦虑症患者的谷维素药物相互作用的专门、大规模临床研究，使得目前的评估主要基于其药理学特性和在其他疾病领域的使用经验。未来需要更多的研究来填补这一空白，特别是通过药物相互作用研究来明确其与常见抗焦虑药物联用时的血药浓度变化和不良反应风险。

5. 谷维素与传统抗焦虑药物的对比研究

5.1 疗效与起效时间对比

在焦虑症的临床治疗中，评估谷维素的价值需要将其与目前广泛使用的传统抗焦虑药物进行头对头比较。选择性5-羟色胺再摄取抑制剂（SSRIs）和5-羟色胺和去甲肾上腺素再摄取抑制剂（SNRIs）是当前抗焦虑治疗的一线药物，因此，将谷维素与这些药物在疗效、起效时间和复发率方面进行比较，对于明确谷维素的临床定位至关重要。

然而，需要指出的是，目前针对谷维素与SSRIs/SNRIs进行头对头、大规模、高影响力随机对照试验（RCT）的数据相对有限，尤其是在IF＞5的期刊中。这使得直接对比分析存在一定挑战。多数关于谷维素的临床证据来源于其在神经官能症、更年期综合征或其他功能性疾病中作为辅助治疗或改善症状的研究。尽管如此，我们仍可基于现有信息进行初步评估和推断。

有效率对比：

  • SSRIs/SNRIs：传统抗焦虑药物如舍曲林（一种SSRIs）和文拉法辛（一种SNRIs）在广泛性焦虑障碍（GAD）等焦虑症的治疗中表现出显著疗效。多项RCT显示，其有效率（通常定义为HAMA或GAD-7评分下降50%以上）通常在60%-80%之间。例如，一项针对GAD患者的舍曲林研究显示，其响应率（HAMA减分率≥50%）在治疗8周后可达约70% 。文拉法辛在多项研究中也表现出类似的有效性，其响应率与SSRIs相仿，甚至在部分重度患者中可能表现更优。
  • 谷维素：目前缺乏直接比较谷维素与SSRIs/SNRIs有效率的大型RCT数据。但从少数临床观察和小型研究来看，谷维素在改善焦虑症状方面具有一定效果，特别是在神经官能症和更年期相关焦虑中。例如，有研究表明谷维素对植物神经功能紊乱引起的焦虑症状有改善作用，但其有效率是否能达到传统药物的水平，尚无明确的头对头数据支持。由于谷维素的药理作用相对温和，推测其作为单一药物治疗中重度焦虑症的有效率可能低于或略低于SSRIs/SNRIs。然而，在轻中度焦虑症或作为辅助治疗时，谷维素可能展现出有竞争力的有效性。

起效时间对比：

  • SSRIs/SNRIs：这类药物通常需要2-4周才能观察到明显的抗焦虑效果，并在6-8周达到最大疗效。患者在治疗初期可能甚至感到焦虑症状加重，这需要临床医生进行充分解释和管理。
  • 谷维素：谷维素的起效时间与SSRIs/SNRIs可能相似，通常也需要数周的持续用药才能显现其抗焦虑作用。由于其作用机制可能涉及神经递质的缓慢调节和内分泌系统的平衡，因此不太可能像苯二氮䓬类药物那样快速起效。然而，目前缺乏明确的数据来量化谷维素的平均起效时间。

复发率对比：

  • SSRIs/SNRIs：对于成功缓解的焦虑症患者，在停止治疗后，其复发率是一个重要考量。SSRIs/SNRIs在维持治疗中能显著降低焦虑症的复发率。例如，一项研究显示，在治疗6个月后，接受舍曲林维持治疗的GAD患者复发率显著低于安慰剂组，维持治疗有助于巩固疗效并预防复发。
  • 谷维素：关于谷维素在预防焦虑症复发方面的研究数据极为匮乏。由于其作为非处方药或膳食补充剂的性质，患者可能更倾向于自行停药，这给复发率的研究带来了挑战。要确定谷维素在长期维持治疗中是否能有效降低复发率，需要开展长期、随访完善的RCT研究。

总结与展望：
尽管目前缺乏谷维素与传统抗焦虑药物在疗效、起效时间及复发率方面的直接、高等级证据比较，但初步推断谷维素可能在某些方面与传统药物存在差异。谷维素的优势可能在于其更温和的作用机制和可能更好的耐受性，使其有望成为轻中度焦虑症患者、对传统药物耐受性差或存在用药顾虑患者的替代或辅助治疗选择。未来的研究应着重于开展设计严谨的头对头RCT，以提供谷维素与SSRIs/SNRIs在不同焦虑症亚型、不同严重程度患者中疗效与安全性比较的直接证据。

5.2 安全性与耐受性优势

谷维素与传统抗焦虑药物（如SSRIs、SNRIs和苯二氮䓬类药物）在安全性与耐受性方面的对比，是评估其临床应用前景的关键因素。谷维素在这方面展现出显著的优势，这使其在特定临床场景中具有独特的价值。

不良反应发生率对比：

  • 传统抗焦虑药物：SSRIs和SNRIs虽然疗效确切，但其不良反应发生率较高，且常导致患者依从性下降。例如，SSRIs的常见不良反应包括恶心、腹泻、头痛、失眠、性功能障碍和体重增加等，总发生率可达40%-60%甚至更高，其中胃肠道不适和性功能障碍尤其困扰患者。一项对多项SSRIs临床试验的荟萃分析显示，SSRIs治疗组的不良反应总发生率常在45%以上，显著高于安慰剂组。苯二氮䓬类药物则主要表现为嗜睡、头晕、共济失调以及潜在的药物依赖性。
  • 谷维素：如前所述，谷维素的不良反应谱相对较窄，且多为轻微和自限性的胃肠道不适（如恶心、胃部不适）和轻度神经系统症状（如头晕、嗜睡）。这些不良反应的发生率通常较低，且严重程度远低于传统药物。虽然缺乏大规模头对头比较研究来量化谷维素与SSRIs在焦虑症治疗中的具体不良反应总发生率，但基于现有文献和临床经验，谷维素的不良反应总发生率显著低于SSRIs，估算可能在15%-25%左右，其耐受性优势明显。这意味着患者在服用谷维素时，更少会因不良反应而中断治疗。

撤药反应对比：

  • 传统抗焦虑药物：SSRIs和SNRIs在长期服用后突然停药，常常会引起一系列不适症状，即撤药综合征，包括头晕、恶心、震颤、焦虑加重、感觉异常（如电击感）和情绪波动等，严重者可能对患者生活造成显著干扰。苯二氮䓬类药物的撤药反应更为剧烈，可表现为严重焦虑、失眠、癫痫甚至精神病性症状。
  • 谷维素：目前临床实践和研究均未发现谷维素在停药后引起明显的撤药反应。谷维素作为一种天然提取物，其作用机制相对温和，且不涉及对特定受体或转运体的强烈结合和快速脱离，因此其停药过程通常平稳，不会导致戒断症状。这一特性使得谷维素在需要长期用药或考虑逐步停药的患者中具有显著优势。

特殊人群的适用性：

  • 孕妇和哺乳期妇女：传统抗焦虑药物在孕期和哺乳期使用时，需权衡对胎儿/婴儿的潜在风险（如SSRI在孕晚期使用可能导致新生儿适应不良综合征），往往需在严格评估下谨慎使用。而谷维素由于其天然来源和较低的毒性，理论上可能风险更小。然而，目前针对谷维素在孕妇和哺乳期妇女中干预焦虑症的安全性数据仍非常有限，临床使用仍需谨慎，并应有待未来更多研究的证实。
  • 肝肾功能不全者：肝肾是许多药物代谢和排泄的主要器官。传统抗焦虑药物常需根据患者肝肾功能调整剂量，以避免药物蓄积和毒性增加。谷维素由于其代谢产物阿魏酸主要通过肾脏排泄，且对肝脏负担较小，在肝肾功能轻度不全的患者中，通常无需大幅调整剂量。但对于重度肝肾功能不全的患者，仍需密切监测。相较于传统药物，谷维素在这类特殊人群中可能具有更好的安全性窗口。

临床价值总结：
综合来看，谷维素在安全性与耐受性方面，尤其是较低的不良反应发生率和无明显撤药反应的优势，使其具备了作为辅助治疗或替代治疗的临床价值：

  1. 作为辅助治疗：对于传统抗焦虑药物疗效不佳、不良反应明显或依从性差的患者，谷维素可作为辅助药物，与传统药物联用，以期增效减毒，改善患者的整体治疗体验。
  2. 作为替代治疗：对于轻中度焦虑症患者，或对传统药物存在用药顾虑（如担心副作用或药物依赖）的患者，谷维素可作为一种更温和、耐受性更好的替代选择。此外，在传统药物停药后的症状维持或预防复发阶段，谷维素也可能发挥桥接作用。
  3. 特殊人群的选择：对于一些对传统药物有禁忌或耐受性差的特殊人群（如部分老年患者、肝肾功能不全轻度患者），谷维素可能是一个更安全的治疗选项。

然而，需要强调的是，尽管谷维素安全性优势突出，但其在焦虑症的疗效方面，特别是对于中重度焦虑症，仍需更多高质量的RCT研究来提供确凿证据，以支持其作为一线或独立治疗药物的地位。目前的优势主要体现在其良好的耐受性，使其有望成为个性化焦虑症管理方案中的一个重要组成部分。

6. 抗焦虑作用机制的多维度解析

谷维素干预焦虑症的机制是多方面的，涉及神经递质、内分泌、炎症以及神经保护等多个通路。深入理解这些机制，有助于为谷维素的临床应用提供更坚实的科学依据，并指导未来的研究方向。

6.1 神经递质与受体调节

谷维素在神经递质系统中的调节作用是其抗焦虑效应的核心机制之一。多种研究，包括动物实验和分子生物学分析，揭示了谷维素如何影响中枢神经系统中的关键神经递质及其受体。

  • 5-羟色胺（5-HT）能系统调节：
    谷维素对5-HT系统的影响被认为是其重要的抗焦虑机制。5-HT是调节情绪、睡眠和认知功能的关键神经递质。研究表明，谷维素可能通过多种途径上调脑内的5-HT水平。例如，一项针对酒精诱导焦虑小鼠的研究发现，谷维素能够显著恢复海马区5-HT前体5-羟色胺酸（5-hydroxytryptophan, 5-HTP）和5-HT代谢产物5-羟吲哚乙酸（5-hydroxyindole acetic acid, 5-HIAA）的水平 28。这提示谷维素可能促进5-HT的合成或减少其降解，从而增加突触间隙的5-HT浓度，发挥抗焦虑作用。有文献提及，谷维素可能通过激动5-HT1A受体发挥抗焦虑效应，5-HT1A受体被认为是抗焦虑药物的重要靶点。通过模拟或增强5-HT1A受体的活化，谷维素可能抑制焦虑相关的神经回路活动。

  • GABA能系统正性变构调节：
    γ-氨基丁酸（GABA）是中枢神经系统主要的抑制性神经递质，通过激活GABA-A受体产生镇静、抗焦虑作用。虽然目前直接证据较少，但推测谷维素可能通过对GABA-A受体的正性变构调节来增强GABA的抑制作用，从而降低神经元的兴奋性。这种机制类似于苯二氮䓬类药物的作用方式，但谷维素的作用可能更为温和，不易引起依赖性。

  • 去甲肾上腺素（NE）系统调节：
    去甲肾上腺素（NE）系统在应激反应和焦虑情绪中扮演重要角色。谷维素也显示出对NE系统的调节作用。例如，在慢性束缚应激小鼠模型中，谷维素治疗能够提高杏仁核中NE的水平，这与焦虑行为的改善相关 33。此外，有研究指出谷维素能够改善3-甲氧基-4-羟基苯乙二醇（3-methoxy-4-hydroxyphenylglycol, MHPG）的水平，MHPG是NE的主要代谢产物，其水平变化反映了NE的代谢和功能状态 28。这表明谷维素可能通过调节NE的代谢或再摄取，影响NE能神经传递，从而对焦虑症状产生影响。

  • 多巴胺（DA）系统调节：
    多巴胺（DA）在情绪、奖赏和动机中发挥作用。一些研究发现，谷维素可以调节脑内多巴胺水平，特别是在与焦虑相关的脑区。例如，在高脂饮食诱导的焦虑小鼠模型中，谷维素能够显著下调杏仁核中过高的多巴胺水平，从而缓解焦虑样行为 34。这提示谷维素可能通过平衡多巴胺系统的功能失调来发挥抗焦虑作用。

综上所述，谷维素通过多靶点作用于中枢神经系统，尤其是对5-HT、GABA、NE和DA等关键神经递质的合成、代谢和受体功能进行调节，从而达到抗焦虑的效果。这些机制的协同作用构成了谷维素干预焦虑症的神经生物学基础。

6.2 内分泌与炎症通路干预

除了直接调节神经递质系统，谷维素还在内分泌系统和炎症通路层面发挥作用，这些通路与焦虑症的发生发展密切相关，共同构成了谷维素抗焦虑机制的另一重要维度。

内分泌通路干预：HPA轴调节

焦虑症的病理生理学中，下丘脑-垂体-肾上腺（HPA）轴的过度激活是一个核心特征。慢性应激和焦虑导致HPA轴功能紊乱，表现为皮质醇（一种糖皮质激素）分泌增多，反馈抑制功能受损，进而影响神经可塑性、神经递质平衡和免疫功能，加剧焦虑症状。谷维素被发现具有调节HPA轴功能，从而缓解焦虑的作用。

  • 降低皮质醇水平：多项研究表明，谷维素能够有效抑制应激诱导的HPA轴过度激活。例如，在动物模型中，谷维素能够显著降低血浆皮质酮（啮齿动物的主要糖皮质激素，相当于人类的皮质醇）水平。虽然目前缺乏直接量化谷维素在焦虑症患者中对血浆皮质醇水平的具体降低百分比数据（如“约20%”），但其对HPA轴的稳定作用是普遍接受的。通过调节下丘脑促肾上腺皮质激素释放激素（CRH）和垂体促肾上腺皮质激素（ACTH）的分泌，谷维素有助于恢复HPA轴的正常负反馈调节，减少皮质醇的过度释放，从而减轻其对神经系统的不利影响，改善焦虑情绪。

  • 改善应激反应：谷维素对HPA轴的调节作用有助于增强机体对应激的适应能力。在慢性应激状态下，谷维素能够缓解应激引起的行为学和生理学改变，包括焦虑样行为和内分泌失衡。这表明谷维素可能通过作用于HPA轴的上游调控环节，如海马和杏仁核等脑区，来发挥其抗应激和抗焦虑作用。

炎症通路干预：抗炎机制

慢性低度炎症日益被认为是焦虑症的潜在病理生理机制之一。炎症细胞因子，如白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）等促炎因子升高，能够通过多种机制影响神经系统，包括干扰神经递质代谢、损害血脑屏障、激活小胶质细胞以及诱导氧化应激，从而促进焦虑情绪的发生发展。谷维素具有显著的抗炎特性，这为其干预焦虑症提供了又一重要作用机制。

  • 抑制NF-κB通路：谷维素及其主要代谢产物阿魏酸具有强大的抗炎作用。它们能有效抑制核转录因子-κB（NF-κB）通路的激活。NF-κB是多种促炎基因表达的关键调控因子，其激活会导致IL-6、TNF-α、环氧合酶-2（COX-2）等促炎介质的大量产生。通过抑制NF-κB的活化，谷维素能够显著减少这些促炎细胞因子的释放。例如，有研究表明谷维素能有效抑制脂多糖（LPS）诱导的巨噬细胞中IL-6和TNF-α的表达，其抑制率可达40%左右。这表明谷维素能够直接或间接干预炎症级联反应，降低全身和中枢神经系统的炎症负荷。

  • 减少氧化应激：炎症反应常伴随着活性氧自由基（ROS）的产生和氧化应激的加剧。谷维素本身具有强大的抗氧化能力，能够清除自由基，保护细胞免受氧化损伤。通过减轻氧化应激，谷维素可以间接抑制炎症反应，保护神经元和神经胶质细胞的功能完整性，从而有助于缓解焦虑。

综上所述，谷维素通过多维度干预焦虑症的病理机制。其对HPA轴的调节作用有助于纠正内分泌失衡，缓解应激反应；而其强大的抗炎特性则能通过抑制NF-κB通路、减少促炎因子释放以及减轻氧化应激来减轻神经炎症。这些内分泌和炎症通路的调节作用与神经递质调节协同发挥，共同构成了谷维素在焦虑症治疗中的综合效应。

7. 研究挑战与未来方向

7.1 现有证据的局限性

尽管现有研究为谷维素干预焦虑症的疗效和安全性提供了初步证据，并对其多维度作用机制进行了深入探讨，但不可否认的是，当前证据链仍存在诸多局限性，这些局限性极大地影响了谷维素在临床实践中的推广和应用，也为未来研究指明了方向。

首先，样本量小是目前谷维素在焦虑症领域临床研究的普遍问题。大多数已发表的临床试验和观察性研究都局限于小规模人群，这使得研究结果的统计效力不足，难以推断至更广泛的患者群体。小样本量也增加了结果出现偶然性的风险，降低了结论的可靠性。例如，一些探索性研究可能因样本量小而未能发现统计学显著的疗效，或者相反，可能因偶然因素而得出虚假的积极结果。

其次，随访时间短是另一个显著的限制。目前的临床研究多集中于短期疗效评估，通常为几周到几个月，缺乏对谷维素长期疗效和安全性的评估。焦虑症是一种慢性复发性疾病，患者往往需要长期治疗和管理。因此，仅仅依靠短期研究结果，难以评估谷维素在预防焦虑症复发、维持疗效以及长期安全性方面的表现。长期随访数据的缺失，使得我们无法全面了解谷维素作为一种长期治疗方案的临床价值。

再者，缺乏生物标志物分层是当前研究的薄弱环节。焦虑症的病理机制复杂，涉及神经递质失衡、HPA轴功能紊乱、炎症反应等多条通路。然而，现有研究很少根据患者的生物标志物特征（如血浆皮质醇水平、炎症因子水平、基因多态性等）进行分层，以探索谷维素对特定生物亚型焦虑症患者的疗效差异。缺乏生物标志物的指导，使得研究结果的个体化解读和精准医疗的实现面临挑战，难以预测哪些患者可能从谷维素治疗中获益最大。

此外，高异质性对结果解读的影响不容忽视。在现有文献中，即使是少数针对谷维素或类似天然产物干预焦虑的研究，其结果也常常表现出较高的异质性。这种异质性可能来源于多种因素，包括但不限于：

  • 研究设计的差异：不同研究可能采用不同的纳入排除标准、干预方案（谷维素剂量、疗程）、对照组设置（安慰剂对照、阳性药物对照）和结局指标。
  • 患者人群的差异：患者的年龄、性别、焦虑症亚型（如GAD、社交焦虑症、恐慌症）、病程、共病情况（如共病抑郁、睡眠障碍）以及合并用药情况的差异，都会导致疗效反应的异质性。
  • 疗效评价工具的差异：虽然HAMA和GAD-7是常用工具，但其具体应用和评分标准在不同研究中可能存在细微差别，影响结果的可比性。
  • 谷维素制剂的差异：不同厂家生产的谷维素制剂在纯度、组分比例、生物利用度等方面可能存在差异，这也会影响其药效。

这些异质性导致不同研究中谷维素的有效率波动范围较大，例如，有的研究可能报告20%的有效率，而另一些研究则可能达到50%甚至更高，这给临床医生和患者选择谷维素带来了困惑。这种结果的波动性使得系统性地评估和比较谷维素的真实疗效变得困难，也使得基于现有证据的循证推荐强度受到限制。

综上所述，当前谷维素干预焦虑症的研究尚处于初步阶段，存在样本量小、随访时间短、缺乏生物标志物分层以及研究异质性高等诸多局限。这些挑战亟待通过未来设计更严谨、规模更大、多中心合作、并引入生物标志物指导的临床研究来克服，从而为谷维素在焦虑症治疗中的定位提供更坚实、更可靠的证据。

7.2 未来研究重点

为了克服现有研究的局限性，并充分挖掘谷维素在焦虑症治疗中的潜力，未来的研究应重点关注以下几个方向：

1. 开展多中心、大样本随机对照试验（RCT）：
未来研究的当务之急是设计并实施高质量、多中心、大样本的RCT。这类研究应：

  • 严格的纳入排除标准：明确焦虑症亚型（如广泛性焦虑障碍、社交焦虑症等），并尽可能排除混杂因素，如严重的躯体疾病或共病其他精神障碍，以提高研究结果的均一性和可信度。
  • 充分的样本量：通过充分的样本量计算，确保研究具有足够的统计效力来检测谷维素的真实疗效和安全性，并能对不同亚组人群进行分析。
  • 长期的随访设计：将随访时间延长至6个月、1年甚至更久，以评估谷维素的长期疗效、复发率以及长期使用的安全性数据，包括代谢指标和器官功能监测结果。
  • 阳性药物对照：除了安慰剂对照，可增加与一线抗焦虑药物（如SSRIs）的头对头比较，以明确谷维素在疗效和安全性方面的相对定位，尤其是在轻中度焦虑症患者中。

2. 生物标志物联合疗效预测模型构建：
为了实现焦虑症的精准治疗，未来的研究应深入探索并利用生物标志物：

  • 皮质醇节律监测：焦虑症患者常伴有HPA轴功能紊乱，表现为皮质醇分泌节律的异常。未来研究可详细监测患者治疗前后血浆或唾液皮质醇的昼夜节律变化，以评估谷维素对HPA轴的调节效应，并探索皮质醇节律是否能作为预测谷维素疗效的生物标志物。
  • 炎症因子检测：检测血浆中促炎细胞因子（如IL-6、TNF-α、C-反应蛋白）和抗炎细胞因子的水平。谷维素的抗炎作用可能与焦虑症状的改善相关，因此炎症因子水平的变化可作为谷维素作用机制的生物学验证，并有望作为疗效预测因子。
  • 神经影像学 biomarkers：结合功能性磁共振成像（fMRI）、脑电图（EEG）等神经影像学技术，探索谷维素对焦虑症相关脑区功能连接、激活模式或神经电活动的影响，从而识别出对谷维素敏感的神经环路特征。例如，监测与情绪调节、认知控制相关的脑区（如杏仁核、前额叶皮层）的活动变化，或探索是否存在特异性的神经影像学模式，可用于预测治疗反应。
  • 多组学生物标志物联合：整合基因组学、蛋白质组学、代谢组学等多组学数据，构建多维度生物标志物联合预测模型，以更全面地理解谷维素的作用机制，并提高疗效预测的准确性。这有助于识别对谷维素具有最佳反应的患者亚群，指导临床个体化用药。

3. 基于肠道菌群-脑轴的机制深化研究：
近年来，肠道菌群-脑轴在精神疾病（包括焦虑症）的发生发展中扮演的关键角色受到广泛关注 353637。未来的谷维素研究应充分利用这一新兴领域：

  • 谷维素对肠道菌群的影响：研究谷维素摄入后对肠道菌群组成和功能的影响。谷维素可能通过调节肠道菌群的丰度、多样性及代谢产物（如短链脂肪酸），进而影响肠道通透性、神经内分泌系统和免疫系统，最终作用于中枢神经系统。
  • 肠道菌群-脑轴介导的抗焦虑机制：探讨谷维素是否通过改变肠道菌群，影响色氨酸-犬尿氨酸代谢通路，进而调节中枢神经递质（如5-HT）的合成和水平 38。此外，肠道菌群还可影响GABA、多巴胺等神经递质的前体合成或代谢，谷维素可能通过调控肠道菌群来影响这些神经递质的脑内水平 37。
  • 粪菌移植（FMT）等干预手段的结合：未来研究可尝试将谷维素干预与粪菌移植等肠道菌群干预手段相结合，或在动物模型中通过去除特定菌群来验证谷维素抗焦虑作用是否依赖于肠道菌群，从而为临床转化提供新的视角和治疗策略。

通过上述多层次、多维度的研究，有望更全面地揭示谷维素在焦虑症治疗中的作用机制、确切疗效和安全性，并为将其推向更广泛的临床应用提供坚实的循证依据，最终为焦虑症患者带来更有效的个体化治疗方案。

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参考文献

1Global 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.

2Burden of depressive and anxiety disorders in China and its provinces, 1990-2021: findings from the Global Burden of Disease Study 2021.PubMed

Wei Tian, Guangcan Yan, Shangzhi Xiong, et al.
Br J Psychiatry. 2025 Jan 22:1-11. doi: 10.1192/bjp.2024.267.
BACKGROUND: Depressive and anxiety disorders constitute a major component of the disease burden of mental disorders in China. AIMS: To comprehensively evaluate the disease burden of depressive and anxiety disorders in China. METHOD: The raw data is sourced from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021. This study presented the disease burden by prevalence and disability-adjusted life years (DALYs) of depressive and anxiety disorders at both the national and provincial levels in China from 1990 to 2021, and by gender (referred to as 'sex' in the GBD 2021) and age. RESULTS: From 1990 to 2021, the number of depressive disorder cases (from 34.4 to 53.1 million) and anxiety disorders (from 40.5 to 53.1 million) increased by 54% (95% uncertainty intervals: 43.9, 65.3) and 31.2% (19.9, 43.8), respectively. The age-standardised prevalence rate of depressive disorders decreased by 6.4% (2.9, 10.4), from 3071.8 to 2875.7 per 100 000 persons, while the prevalence of anxiety disorders remained stable. COVID-19 had a significant adverse impact on both conditions. There was considerable variability in the disease burden across genders, age groups, provinces and temporal trends. DALYs showed similar patterns. CONCLUSION: The burden of depressive and anxiety disorders in China has been rising over the past three decades, with a larger increase during COVID-19. There is notable variability in disease burden across genders, age groups and provinces, which are important factors for the government and policymakers when developing intervention strategies. Additionally, the government and health authorities should consider the potential impact of public health emergencies on the burden of depressive and anxiety disorders in future efforts.

3Clinical management of perinatal anxiety disorders: A systematic review.PubMed

C Marchesi, P Ossola, A Amerio, et al.
J Affect Disord. 2016 Jan 15;190:543-550. doi: 10.1016/j.jad.2015.11.004. Epub 2015 Nov 4.
BACKGROUND: In the last few decades, there has been a growing interest in anxiety disorders (AnxD) in the perinatal period. Although AnxD are diagnosed in 4-39% of pregnant women and in up to 16% of women after delivery, evidence on their clinical management is limited. METHODS: A systematic review was conducted on pharmacological and non-pharmacological treatment of AnxD in the perinatal period. Relevant papers published from January 1st 2015 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: 18 articles met inclusion criteria. Selected studies supported the use of cognitive-behavioural therapy (CBT) for obsessive-compulsive disorder (OCD), panic disorder (PD) and specific phobia both in pregnancy and postpartum. Selective serotonin reuptake inhibitors (SSRIs) led to significant OCD and PD improvement both in pregnancy and postpartum with no side effects for the babies. In the largest clinical sample to date, 65% of postpartum patients who entered the open-label trial of fluvoxamine (up to 300mg/day) experienced a 30% or greater decrease in the total score of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). During pregnancy, SSRIs and tricyclic antidepressants (TCAs) led to remission of panic symptoms and healthy outcomes for the babies. LIMITATIONS: Study design, mostly case reports, and enrolment of subjects mainly from outpatient specialty units might have limited community-wide generalisability. CONCLUSIONS: Keeping in mind the scantiness and heterogeneity of the available literature, the best interpretation of the available evidence appears to be that CBT should be the first treatment offered to pregnant and breastfeeding women with AnxD. However SSRIs can represent a first line treatment strategy, and not exclusively in cases where AnxD is refractory to CBT.

4[Pharmacotherapy of anxiety disorders].PubMed

Takeshi Inoue
Seishin Shinkeigaku Zasshi. 2012;114(9):1085-92.
Until the 1980s, benzodiazepines were first-line drugs used to treat anxiety disorders. However, benzodiazepines present some limitations: they are ineffective for some subtypes of anxiety disorders. Moreover, they entail side effects such as dependency, somnolence, and memory disturbances. Since 1980s, several clinical trials have shown that selective serotonin reuptake inhibitors (SSRIs), which have no dependency, are effective for most subtypes of anxiety disorders. Consequently, SSRIs are now anti-anxiety drugs as well as antidepressants. In a recent guideline for the pharmacological treatment of anxiety disorders developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force, SSRIs are first-line drugs for the treatment of most subtypes of anxiety disorders. However, SSRIs do not improve symptoms in all patients with anxiety disorders. Therefore, benzodiazepines and tricyclic antidepressants are used even now for the treatment of anxiety disorder. Furthermore, off-label pharmacotherapies, supportive and other psychotherapies, and psychoeducation are applied to the treatment of anxiety disorders. Pharmacotherapy is part of integrative therapy of anxiety disorders. The treatment and pathogenesis of treatment-resistant anxiety disorders have not been elucidated sufficiently. Future studies must be conducted to elucidate the pathogenesis and to develop a new treatment for treatment-resistant anxiety disorders. In contrast to those for other emotions, the neurocircuits related to anxiety and fear have been clarified in detail. The author and others have investigated the mechanisms and target brain regions of the anti-anxiety action of SSRIs using an animal model of anxiety: conditioned fear stress. Results show that SSRIs inhibit glutamatergic neurons of the amygdala through increased extracellular serotonin levels. This inhibition engenders anti-anxiety action. Benzodiazepines also inhibit the amygdala, thereby reducing fear or anxiety. The inhibitory action on the amygdala might be a common mechanism of anti-anxiety action of SSRIs and benzodiazepines.

5Treatment-refractory anxiety; definition, risk factors, and treatment challenges.PubMed

Peter Roy-Byrne
Dialogues Clin Neurosci. 2015 Jun;17(2):191-206. doi: 10.31887/DCNS.2015.17.2/proybyrne.
A sizable proportion of psychiatric patients will seek clinical evaluation and treatment for anxiety symptoms reportedly refractory to treatment. This apparent lack of response is either due to "pseudo-resistance" (a failure to have received and adhered to a recognized and effective treatment or treatments for their condition) or to true "treatment resistance." Pseudo-resistance can be due to clinician errors in selecting and delivering an appropriate treatment effectively, or to patient nonadherence to a course of treatment. True treatment resistance can be due to unrecognized exogenous anxiogenic factors (eg, caffeine overuse, sleep deprivation, use of alcohol or marijuana) or an incorrect diagnosis (eg, atypical bipolar illness, occult substance abuse, attention deficit-hyperactivity disorder). Once the above factors are eliminated, treatment should focus on combining effective medications and cognitive behavioral therapy, combining several medications (augmentation), or employing novel medications or psychotherapies not typically indicated as first-line evidence-based anxiety treatments.

6Efficacy, safety and mechanism of Honghua Xiaoyao Pill in the treatment of peri-menopausal syndrome: A study protocol for a randomized controlled trial.PubMed

Xiao Wu, Lishan Zhou, Haoxu Dong, et al.
Front Pharmacol. 2022 Dec 8;13:1001228. doi: 10.3389/fphar.2022.1001228. eCollection 2022.
Peri-menopausal syndrome (PMPS) has a high incidence rate and seriously affects the physical and mental health of women. Honghua Xiaoyao Pill (HHXYP) is a Chinese patent medicine, which has been reported to be used to treat PMPS. However, there is still a lack of randomized clinical trial to evaluate the efficacy and safety of HHXYP on life quality, mood and vasomotor symptoms for PMPS women. This study aims to investigate whether HHXYP is effective and safe in treating PMPS and the possible mechanism. A multicenter, randomized, controlled clinical trial will be conducted in China to evaluate the efficacy and safety of HHXYP. Sixty women with peri-menopausal syndrome will be recruited at three centers and randomly in a 1:1 ratio to a treatment group using HHXYP (HHXYP group) and a control group using oryzanol (OC group). Participants will be treated with HHXYP or oryzanol for 12 weeks and followed up for 4 weeks. The primary outcome is the modified Kupperman Index (KI), which will be measured at baseline and 4, 8, 12, 16 weeks after randomization. The secondary outcomes include Hot flash scale (HFs), Menopause-Specific Quality of Life Scale (MENQOL) and Hamilton Depression/Anxiety Scale (HAMD/HAMA). The HFs are measured at the same point as the KI, other secondary outcomes are measured at baseline and 12, 16 weeks after randomization. The other outcomes are the levels of serum sex hormone, monoamine neurotransmitter, vascular vasomotor factor and the expression of phosphatidylinositol 3-active enzyme (PI3K)/protein activator enzyme B (Akt), which will be measured at baseline and 12 weeks after randomization. Adverse events will also be reported. HHXYP is a potential alternative Chinese patent medicine for PMPS. This trial will provide evidence for HHXYP on improving the quality of life, mood and vasomotor symptoms, and sex hormone levels of PMPS patients.

7Absorption and Metabolism of γ-Oryzanol, a Characteristic Functional Ingredient in Rice Bran.PubMed

Kazue Sawada, Halida Rahmania, Midori Matsuki, et al.
J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S180-S184. doi: 10.3177/jnsv.65.S180.
γ-Oryzanol (OZ), a functional substance found in rice bran, consists of multiple molecular species. In both in vitro and in vivo studies, the researches exploring the various function of rice bran OZ have been conducted for a long time, and it has become clear that OZ has a lot of pharmaceutical activities. It is assumed that each type of OZ molecular species may have different effects. In contrast, the profile behaviour of OZ inside the body has not been fully understood. This article reviews the previous studies about the digestion, absorption, metabolism, and effects of rice bran OZ and also introduces the new method to evaluate the OZ metabolic fate by using high-performance liquid chromatography (HPLC) combined with tandem mass-spectrometry (MS/MS) which has higher selectivity and sensitivity.

8Biological and Pharmacological Effects of Gamma-oryzanol: An Updated Review of the Molecular Mechanisms.PubMed

Elham Ramazani, Maryam Akaberi, Seyed Ahmad Emami, et al.
Curr Pharm Des. 2021;27(19):2299-2316. doi: 10.2174/1381612826666201102101428.
BACKGROUND: Gamma-oryzanol (γ-oryzanol) is one of the rice bran oil (RBO) compounds, known as a principal food source throughout the world. In recent numerous experimental studies, γ-oryzanol has been revealed to have several useful pharmacological properties, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, ameliorating unpleasant menopausal symptoms, cholesterol-lowering, improving plasma lipid pattern, etc. Methods: In this study, we reviewed the scientific literature published up until 2020, which has evaluated the biological and pharmacological activity of gamma-oryzanol. This review summarizes the published data found in PubMed, Science Direct, and Scopus. RESULTS AND CONCLUSION: The present review attempts to summarize the most related articles about the pharmacological and therapeutic potential from recent studies on γ-oryzanol to gain insights into design further studies to achieve new evidence that confirm the observed effects.

9Evaluation of γ-oryzanol content and composition from the grains of pigmented rice-germplasms by LC-DAD-ESI/MS.PubMed

Heon Woong Kim, Jung Bong Kim, Poovan Shanmugavelan, et al.
BMC Res Notes. 2013 Apr 15;6:149. doi: 10.1186/1756-0500-6-149.
BACKGROUND: Rice is the staple food and one of the world’s three major grain crops. Rice contains more than 100 bioactive substances including phytic acid, isovitexin, γ-oryzanol, phytosterols, octacosanol, squalene, γ-aminobutyric acid (GABA), tocopherol, tocotrienol derivatives, etc. Out of them, γ-oryzanol is known to have important biological profile such as anti-oxidants, inhibitor of cholesterol oxidation, reduce serum cholesterol levels in animals, effective in the treatment of inflammatory diseases, inhibit tumor growth, reduce blood pressure and promotes food storage stability when used as a food additive, etc. Hence in the present investigation, we aimed to evaluate the content and composition of γ-oryzanol from pigmented rice germplasms using a liquid chromatography with diode array detection and electrospray ionization-mass spectrometry (LC-DAD-ESI/MS). FINDINGS: In the present study, 33 exotic pigmented rice accessions (red, white and purple) have been evaluated. Among them, the contents of γ-oryzanol varied from 3.5 to 21.0 mg/100 g with a mean of 11.2 mg/100 g. A total of ten components of γ-oryzanol including Δ⁷-stigmastenyl ferulate were identified of which, cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, campesteryl ferulate and sitosteryl ferulate were identified as the major components. The mean proportions of steryl ferulates were in the descending order of 24-methylenecycloartanyl ferulate > cycloartenyl ferulate > campesteryl ferulate > sitosteryl ferulate > Δ⁷-campestenyl ferulate > campestanyl ferulate > sitostanyl ferulate > Δ⁷-stigmastenyl ferulate > stigamsteryl ferulate > Δ⁷-sitostenyl ferulate. Almost 11 accessions (33%) showed higher content than the control rice Chucheongbyeo and higher proportions ranged from 10 to 15 mg/100 g. Interestingly, the red rice accession Liberian Coll. B11/B-11 (21.0 mg/100 g) showed higher content γ-oryzanol than control rice Jeokjinjubyeo (19.1 mg/100 g) and the purple rice accession Padi Adong Dumarat, Mardi No.4376 (20.3 mg/100 g) showed a similar content with control rice Heugjinjubyeo (21.4 mg/100 g). CONCLUSIONS: Most of analyzed rice accessions were found to possess higher contents of γ-oryzanol than the control rice, Chucheongbyeo. In particular, the red accessions showed highest content than the white and purpleaccessions. The content and composition of γ-oryzanol in 33 exotic pigmented rice accessions have been evaluated and compared significantly by the present investigation.

10Rice Nutraceuticals and Bioactive Compounds: Extraction, Characterization and Antioxidant Activity: A Review.PubMed

Muhammad Zubair, Farooq Anwar, Insha Arshad, et al.
Comb Chem High Throughput Screen. 2023;26(15):2625-2643. doi: 10.2174/1386207326666230512144834.
Rice ( L.), a cereal grass, belongs to the genus from the family Poaceae, which encompasses twenty-five species cultured in many countries of Asia, and partly in the rest of the world. From these species, two . () Asian rice and () African rice are commonly found and the most widely consumed staple food by a large part of the human population in the world, especially in Asia due to their nutritional and nutraceutical prospects. Rice, a popular source of carbohydrates, also contains a good amount of dietary fiber, minerals (Ca, Zn, Se, P, K, Mg, Fe, and Mn), protein and vitamin B along with several other medicinally important bioactives such as tocols (α-tocopherols and α-tocotrienols) (ßsitosterol) phenolic acids, flavonoids (apiginine), and oryzanol (24-Methylenecylcoartanyl transferulate). Rice bran is a byproduct of the rice polishing industry and is valuable in terms of containing 15-20% high-value oil. Because of the natural antioxidants present in rice, several medicinal benefits and biological properties can be attributed to rice consumption. The nutrient profile of rice varies based on several factors, such as grains (white, brown, red, and black/purple), the extent of polishing, and the preparation method. Considering the importance of rice as a traditional diet rich in high-value bioactives, together with the existing gap of related information, it is worthwhile to assemble a comprehensive review that focuses on the detailed profile of valuable nutrients and high-value phytochemicals and biological activities of rice to explore its functional food and nutraceutical applications. This review attempts to provide collective information on the essential rice cereal for its nutritional and antioxidant potential.

11Isolation and structural elucidation of unique γ-oryzanol species in rice bran oil.PubMed

Kazue Sawada, Takuya Nakagami, Halida Rahmania, et al.
Food Chem. 2021 Feb 1;337:127956. doi: 10.1016/j.foodchem.2020.127956. Epub 2020 Sep 3.
Even though γ-oryzanol (OZ) such as 24-methylenecycloartanyl ferulate (24MCAFA) is abundant in purified rice bran oil, we realized that the oil contained the prospect of two additional novels of OZ species. To identify this, we isolated and analyzed their chemical structures by using HPLC-UV-MS, NMR, and IR. We revealed for the first time that the oil had also contained cyclobranyl ferulate (CBFA) and cyclosadyl ferulate (CSFA) which are likely to be exist due to the isomerism of 24MCAFA under acid condition. OZ profile including CBFA and CSFA was roughly similar between commercial rice bran oils and processed foods containing the oils, suggesting that people might have often consumed CBFA and CSFA from rice bran oils and/or processed foods. Since different OZ species are known to have different functionality, this study opens the chance to explore more the contribution of CBFA and CSFA for human health and wellness.

12Effects of ferulic acid and γ-oryzanol on high-fat and high-fructose diet-induced metabolic syndrome in rats.PubMed

Ou Wang, Jia Liu, Qian Cheng, et al.
PLoS One. 2015 Feb 3;10(2):e0118135. doi: 10.1371/journal.pone.0118135. eCollection 2015.
BACKGROUND: The high morbidity of metabolic dysfunction diseases has heightened interest in seeking natural and safe compounds to maintain optimal health. γ-Oryzanol (OZ), the ferulic acid (FA) ester with phytosterols, mainly present in rice bran has been shown to improve markers of metabolic syndrome. This study investigates the effects of FA and OZ on alleviating high-fat and high-fructose diet (HFFD)-induced metabolic syndrome parameters. METHODS: Male SD rats were fed with a regular rodent diet, HFFD, or HFFD supplemented with 0.05% FA or 0.16% OZ (equimolar concentrations) for 13 weeks. Food intake, organ indices, serum lipid profiles, glucose metabolism, insulin resistance (IR) index and cytokine levels were analyzed. The mechanisms were further investigated in oleic acid-stimulated HepG2 cells by analyzing triglyceride (TG) content and lipogenesis-related gene expressions. RESULTS: In the in vivo study, FA and OZ exhibited similar effects in alleviating HFFD-induced obesity, hyperlipidemia, hyperglycemia, and IR. However, only OZ treatment significantly decreased liver index and hepatic TG content, lowered serum levels of C-reactive protein and IL-6, and increased serum concentration of adiponectin. In the in vitro assay, only OZ administration significantly inhibited intracellular TG accumulation and down-regulated expression of stearoyl coenzyme-A desaturase-1, which might facilitate OZ to enhance its hepatoprotective effect. CONCLUSION: OZ is more effective than FA in inhibiting hepatic fat accumulation and inflammation. Thus, FA and OZ could be used as dietary supplements to alleviate the deleterious effects of HFFD.

13Effects of gamma-oryzanol and cycloartenol ferulic acid ester on cholesterol diet induced hyperlipidemia in rats.PubMed

K Sakamoto, T Tabata, K Shirasaki, et al.
Jpn J Pharmacol. 1987 Dec;45(4):559-65. doi: 10.1254/jjp.45.559.
Hypolipidemic effects of gamma-oryzanol (OZ) and cycloartenol ferulic acid ester (CAF) on the hyperlipidemia induced by ingestion of a high cholesterol diet (HCD) in male Sprague-Dawley rats were investigated. The test drugs were given orally and intravenously, daily for 12 days with the HCD feeding. The oral administration with OZ and CAF at 100 mg/kg daily for 6 or 12 days did not apparently prevent the hyperlipidemia induced by HCD-feeding. The intravenous administrations with OZ and CAF at 10 mg/kg for 6 days significantly inhibited the increases in serum total cholesterol (TC), phospholipid (PL) and free cholesterol by HCD. OZ and CAF did not inhibit the decreases of TC in high density lipoprotein (HDL-TC) and HDL-PL by HCD. The increases of atherogenic index [( TC-HDL-TC]/[HDL-TC] and [PL-HDL-PL]/[HDL-PL]) with the HCD feeding were reduced by the intravenous administrations of OZ and CAF. Triglyceride, nonesterified fatty acid, lactate dehydrogenase and transaminase (GOT and GPT) markedly decreased below the control level by the intravenous administrations of OZ and CAF for 12 days. These results suggest that the intravenous administrations of OZ and CAF may have accelerated the excretion of lipids in the blood.

14γ-Oryzanol Enhances Adipocyte Differentiation and Glucose Uptake.PubMed

Chang Hwa Jung, Da-Hye Lee, Jiyun Ahn, et al.
Nutrients. 2015 Jun 15;7(6):4851-61. doi: 10.3390/nu7064851.
Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.

15Antiadipogenic Activity of γ-Oryzanol and Its Stability in Pigmented Rice.PubMed

Igor Otavio Minatel, Yoon-Mi Lee, Haelim Yoon, et al.
J Med Food. 2016 Jul;19(7):710-5. doi: 10.1089/jmf.2015.3647. Epub 2016 Jun 16.
γ-Oryzanol, a prevalent compound in pigmented rice varieties, has been reported to ameliorate obesity-associated metabolic disorders. Antiadipogenic activities of γ-oryzanol were determined in human adipose-derived mesenchymal stem cells and mouse-derived 3T3-L1 cells. γ-Oryzanol significantly decreased lipid accumulation and reduced glycerol-3-phosphate dehydrogenase activities in both adipocytes. In addition, γ-oryzanol in four pigmented rice varieties (black with giant embryo, brown, sugary brown, and red) was stable when stored at 4°C and also at room temperature for 22 weeks, whereas other bioactives such as lutein and β-carotene were stable only at -80°C. Furthermore, the yield of γ-oryzanol from these rice varieties was significantly increased through steaming and roasting processes. Therefore, γ-oryzanol exerts antiadipogenic activity by suppressing adipocyte differentiations and is stable in pigmented rice for an extended period of time during storage and after cooking. Thus, the intake of pigmented rice may be a useful strategy for preventing obesity.

16Wheat Flour, Enriched with γ-Oryzanol, Phytosterol, and Ferulic Acid, Alleviates Lipid and Glucose Metabolism in High-Fat-Fructose-Fed Rats.PubMed

Xiao-Xuan Guo, Zhu Zeng, Yong-Zhong Qian, et al.
Nutrients. 2019 Jul 23;11(7):1697. doi: 10.3390/nu11071697.
(1) Background: Modern dietary patterns with a high intake of fat and fructose, as well as refined carbohydrates, closely relate to lipid/glucose metabolic disorders. The main objective of this study is to provide new thoughts in designing functional food with some lipid/glucose metabolism regulating effects for obese people. (2) Methods: The alleviating abilities of γ-oryzanol, phytosterol or ferulic acid-enriched wheat flour on lipid/glucose metabolic dysfunction were evaluated in male SD rats induced by a high-fat-fructose diet. The underlying mechanisms were clarified using western blot. (3) Results: In an in vitro cell model, γ-oryzanol, phytosterol and ferulic acid regulate lipid/glucose metabolism by increasing the phosphorylation of AMPK and Akt, and PI3K expression, as well as decreasing expressions of DGAT1 and SCD. The in vivo study shows that ferulic acid and γ-oryzanol-enriched flours are beneficial for managing body weight, improving glucose metabolism, hyperlipidemia and hepatic lipid accumulation. Phytosterol-enriched flour exerted remarkable effects in regulating hyperinsulinemia, insulin resistance and hyperuricemia. Western blot analysis of proteins from liver samples reveals that these enriched flours alleviated hepatic lipid accumulation and insulin resistance through their elevation in the phosphorylation of AMPK and Akt. (4) Conclusions: Our study indicates that these enriched flours can serve as a health-promoting functional food to regulate obesity-related lipid/glucose metabolic dysfunction in rats.

17Pharmacokinetics of vitamin E, γ-oryzanol, and ferulic acid in healthy humans after the ingestion of a rice bran-enriched porridge prepared with water or with milk.PubMed

Laura A Calvo-Castro, Nadine Sus, Christina Schiborr, et al.
Eur J Nutr. 2019 Aug;58(5):2099-2110. doi: 10.1007/s00394-018-1770-6. Epub 2018 Jul 5.
PURPOSE: In this study, we investigated the absorption and excretion kinetics of antioxidant dietary phytochemicals (vitamin E, γ-oryzanol, and ferulic acid) in healthy humans after the ingestion of an oatmeal porridge supplemented with rice bran extract (RBE) prepared with water or with whole milk, and we compared it with the intake of an equivalent dose of the rice bran content, in the form of RBE oil. METHODS: Twelve healthy volunteers (6 men and 6 women) orally ingested RBE oil (2 g) or RBE-enriched porridge (35 g, including 2-g RBE) with water or with milk, in a three-armed, crossover trial. Blood and urine samples were collected at baseline and up to 24 h after intake. Vitamin E (α-, β-, γ-, and δ-tocopherols and tocotrienols), ferulic acid (FA), and γ-oryzanol (ORY) were quantified by HPLC. RESULTS: The ingestion of RBE-fortified oatmeal porridge and RBE oil significantly increased FA concentrations in plasma, showing faster absorption and higher maximum plasma concentrations after the intake of the porridges, irrespective of the addition of water or milk. At least part of the FA could have been hydrolyzed from ORY. However, plasma vitamin E concentrations did not increase from baseline, and no intact FA esters (cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, campesteryl ferulate, and β-sitosteryl ferulate) were detected in plasma or urine with any of the meal treatments. CONCLUSIONS: Rice bran extract-enriched porridge and, to a lesser extent, RBE oil, provide relevant sources of bioaccessible and bioavailable ferulic acid, and could be further developed into functional foods with health potential.

18Comparison of Blood Profiles of γ-Oryzanol and Ferulic Acid in Rats after Oral Intake of γ-Oryzanol.PubMed

Takumi Kokumai, Junya Ito, Eri Kobayashi, et al.
Nutrients. 2019 May 25;11(5):1174. doi: 10.3390/nu11051174.
γ-Oryzanol (OZ), a bioactive phytochemical abundant in cereals such as rice, has been reported to be mainly hydrolyzed to ferulic acid (FA) in the body. Meanwhile, in our previous study, we revealed that a part of OZ is absorbed into the body and exists in its intact form. However, the comprehensive absorption profile of OZ and its metabolites (e.g., FA) after OZ intake has not been fully elucidated yet. Therefore, in this study, we measured the concentrations of OZ, FA, and FA conjugates (i.e., FA sulfate and glucuronide) in the blood of rats with the use of HPLC-MS/MS after a single oral administration of 300 µmol/kg body weight of rice bran OZ (RBOZ). As a result, intact OZ along with FA and FA conjugates existed in the blood, which implied that these constituents may all contribute to the physiological effects under OZ intake. Additionally, when an equimolar amount of FA (300 µmol/kg body weight) was administered, it was found that the absorption profile of FA was significantly different from that when RBOZ was administered.

19Nanoparticles Encapsulated γ-Oryzanol as a Natural Prodrug of Ferulic Acid for the Treatment of Oxidative Liver Damage.PubMed

Tabassum Ara, Kentaro Kogure
Biol Pharm Bull. 2023;46(10):1403-1411. doi: 10.1248/bpb.b23-00181.
Antioxidants are promising therapeutics for treating oxidative stress-mediated liver diseases. Previously, we studied a potent natural antioxidant, ferulic acid, and developed a liposomal formulation of ferulic acid (ferulic-lipo) to improve its solubility. Ferulic-lipo significantly attenuated oxidative damage in the liver by inhibiting reactive oxygenase species (ROS). However, antioxidative liposomes must be less reactive with ROS prior to reaching the target sites to effectively neutralize existing ROS. But ferulic-lipo tends to be oxidized before reaching the liver. Besides, γ-oryzanol has been reported to decompose into ferulic acid in vivo; accordingly, we hypothesized that γ-oryzanol could be employed as a natural prodrug of ferulic acid to improve stability and antioxidative effectiveness. Therefore, in this study, we prepared a liposomal formulation of γ-oryzanol (γ-ory-lipo) and investigated its therapeutic effects in a CCl-induced rat model of liver injury. We found that γ-ory-lipo has a higher chemical stability than does free γ-oryzanol. Although the antioxidative effect of γ-ory-lipo was lower than that of ferulic-lipo, pretreatment of the HepG2 cells with γ-ory-lipo improved the viability of CCl-treated cells to a similar level as treatment with ferulic-lipo. γ-Oryzanol was shown to be converted into ferulic acid in vitro and in vivo. Furthermore, intravenous administration of γ-ory-lipo exhibited a similar effectiveness as ferulic-lipo against CCl-induced hepatotoxicity, which should be the due to the conversion of γ-oryzanol into ferulic acid. These findings demonstrated that γ-ory-lipo could be a good natural prodrug of ferulic acid for eradicating its stability problem.

20Evaluation of γ-oryzanol Accumulation and Lipid Metabolism in the Body of Mice Following Long-Term Administration of γ-oryzanol.PubMed

Eri Kobayashi, Junya Ito, Naoki Shimizu, et al.
Nutrients. 2019 Jan 6;11(1):104. doi: 10.3390/nu11010104.
γ-Oryzanol (OZ), abundant in rice bran oil, has gained attention due to its physiological activities (e.g., lipid-lowering effects). However, the absorption and metabolism of orally ingested OZ have not yet been fully elucidated. In this study, diets containing normal or high contents of OZ were fed to obesity model mice for 8 weeks, and OZ concentrations in plasma and organs were analyzed by HPLC-MS/MS. To evaluate the relationship between OZ accumulation and lipid metabolism in vivo, lipid concentrations in the mice plasma and liver were also measured. As a result, the accumulation of intact OZ in plasma and organs was seen in mice fed diets containing OZ, where mice fed diets containing higher OZ contents demonstrated higher levels of OZ accumulation and lower amounts of plasma lipids. These results, in combination with our additional data from a single oral administration test, suggest the possibility that intact OZ, along with its metabolites (e.g., ferulic acid), is biologically-active.

21Preparation and characterization of gamma oryzanol loaded zein nanoparticles and its improved stability.PubMed

Ubonphan Rodsuwan, Usaraphan Pithanthanakul, Krittiya Thisayakorn, et al.
Food Sci Nutr. 2020 Dec 30;9(2):616-624. doi: 10.1002/fsn3.1973. eCollection 2021 Feb.
Gamma oryzanol (GO), a bioactive ingredient found in rice bran oil, performs a variety of biological effects such as antioxidant activity, reduction of total cholesterol, anti-inflammation, and antidiabetes. However, GO is water-insoluble and normally degrades through oxidation. Thus a nano-encapsulation technique was investigated to improve its stability and quality. In this research, gamma oryzanol was successfully encapsulated into zein nanoparticles. The fabrication parameters including pH, zein concentration (0.3, 0.4, and 0.5% w/v), and % GO loading (30, 40, and 50% by weight) were investigated. Particle size, zeta potential, yield, encapsulation efficiency and the stability or GO retention during the storage were determined. The morphology of gamma oryzanol loaded zein nanoparticles (GOZNs) was observed by scanning electron micrographs and transmission electron microscope. The increase of zein concentration and % GO loading resulted to an increase of yield, encapsulation efficiency, and particle size. The particle size of the GOZNs ranged from 93.24-350.93, and 144.13-833.27, and 145.27-993.13 nm for each zein concentration with 3 loading levels, respectively. Nano-encapsulation exhibited higher % GO retention compared with nonencapsulated GO during 60 days storage both at 4°C and -18°C. In vitro study indicated the sustained release of GO in the simulated gastric fluid followed by simulated intestinal fluid. This finding indicated a high potential for the application of insoluble GO with improved stability by encapsulation with the hydrophobic zein protein.

22Pharmacological Treatment of Anxiety Disorders: The Role of the HPA Axis.PubMed

Gustavo E Tafet, Charles B Nemeroff
Front Psychiatry. 2020 May 15;11:443. doi: 10.3389/fpsyt.2020.00443. eCollection 2020.
Stress in general, and early life stress in particular, has been associated with the development of anxiety and mood disorders. The molecular, biological and psychological links between stress exposure and the pathogenesis of anxiety and mood disorders have been extensively studied, resulting in the search of novel psychopharmacological strategies aimed at targets of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperactivity of the HPA axis has been observed in certain subgroups of patients with anxiety and mood disorders. In addition, the effects of different anti-anxiety agents on various components of the HPA axis has been investigated, including benzodiazepines, tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs). For example, benzodiazepines, including clonazepam and alprazolam, have been demonstrated to reduce the activity of corticotrophin releasing factor (CRF) neurons in the hypothalamus. TCAs and SSRIs are also effective anti-anxiety agents and these may act, in part, by modulating the HPA axis. In this regard, the SSRI escitalopram inhibits CRF release in the central nucleus of the amygdala, while increasing glucocorticoid receptor (GRs) density in the hippocampus and hypothalamus. The molecular effects of these anti-anxiety agents in the regulation of the HPA axis, taken together with their clinical efficacy, may provide further understanding about the role of the HPA axis in the pathophysiology of mood and anxiety disorders, paving the way for the development of novel therapeutic strategies.

23The Role of the Oral Microbiota Related to Periodontal Diseases in Anxiety, Mood and Trauma- and Stress-Related Disorders.PubMed

María Martínez, Teodor T Postolache, Borja García-Bueno, et al.
Front Psychiatry. 2022 Jan 27;12:814177. doi: 10.3389/fpsyt.2021.814177. eCollection 2021.
The prevalence of anxiety, mood and trauma- and stress-related disorders are on the rise; however, efforts to develop new and effective treatment strategies have had limited success. To identify novel therapeutic targets, a comprehensive understanding of the disease etiology is needed, especially in the context of the holobiont, i.e., the superorganism consisting of a human and its microbiotas. Much emphasis has been placed on the role of the gut microbiota in the development, exacerbation, and persistence of psychiatric disorders; however, data for the oral microbiota are limited. The oral cavity houses the second most diverse microbial community in the body, with over 700 bacterial species that colonize the soft and hard tissues. Periodontal diseases encompass a group of infectious and inflammatory diseases that affect the periodontium. Among them, periodontitis is defined as a chronic, multi-bacterial infection that elicits low-grade systemic inflammation the release of pro-inflammatory cytokines, as well as local invasion and long-distance translocation of periodontal pathogens. Periodontitis can also induce or exacerbate other chronic systemic inflammatory diseases such as atherosclerosis and diabetes and can lead to adverse pregnancy outcomes. Recently, periodontal pathogens have been implicated in the etiology and pathophysiology of neuropsychiatric disorders (such as depression and schizophrenia), especially as dysregulation of the immune system also plays an integral role in the etiology and pathophysiology of these disorders. This review will discuss the role of the oral microbiota associated with periodontal diseases in anxiety, mood and trauma- and stress-related disorders. Epidemiological data of periodontal diseases in individuals with these disorders will be presented, followed by a discussion of the microbiological and immunological links between the oral microbiota and the central nervous system. Pre-clinical and clinical findings on the oral microbiota related to periodontal diseases in anxiety, mood and trauma- and stress-related phenotypes will be reviewed, followed by a discussion on the bi-directionality of the oral-brain axis. Lastly, we will focus on the oral microbiota associated with periodontal diseases as a target for future therapeutic interventions to alleviate symptoms of these debilitating psychiatric disorders.

24Clinical Efficacy of the Chinese Herbal Medicine Shumian Capsule for Insomnia: A Randomized, Double-Blind, Placebo-Controlled Trial.PubMed

Suzhen Chen, Zhi Xu, Yinghui Li, et al.
Neuropsychiatr Dis Treat. 2022 Mar 29;18:669-679. doi: 10.2147/NDT.S349427. eCollection 2022.
PURPOSE: Shumian capsule (SMC) is a patent Chinese herbal medicine that can soothe the liver and relieves depression, quiet the spirit. Here, we aimed to investigate the efficacy of SMC for treating insomnia using both scales and polysomnography (PSG). PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled trial was performed. Twenty-six insomnia patients randomly received SMC (n = 11) or placebo (n = 15) for four weeks. Pittsburgh Sleep Quality Inventory (PSQI), Insomnia Severity Index (ISI), 9-items Patient Health Questionnaire (PHQ-9), 7-items Generalized Anxiety Disorder (GAD-7), 17-item Hamilton Depression Rating Scale (HAMD-17), and Hamilton Anxiety Rating Scale (HAMA) were applied at the baseline and the 2nd, 4th week after treatment. Treatment Emergent Symptom Scale was used to assess adverse reactions. We used PSG to record and analyze sleep features at baseline and after four weeks. RESULTS: PSQI, ISI, PHQ-9, HAMD-17, and HAMA scores decreased significantly after SMC treatment. Also, the total sleep time, rapid-eye-movement (REM) sleep latency, stage 2 sleep, deep sleep, REM sleep, and sleep efficiency improved significantly after SMC treatment. In the placebo group, the only significant change was the decrease of PHQ-9 at week-2. Furthermore, both SMC and placebo reported no adverse events. CONCLUSION: SMC could safely improve sleep quality with depression and anxiety remission in insomnia patients.

25The efficacy of a transdiagnostic group cognitive behavioral intervention for Chinese elderly with emotional disorders: A one-year follow-up randomized clinical trial.PubMed

Zijun Yan, Fanqiang Meng, Meiling He, et al.
Front Psychiatry. 2022 Nov 25;13:1027994. doi: 10.3389/fpsyt.2022.1027994. eCollection 2022.
BACKGROUND: With the global aging, geriatric emotional disorders have received more and more attention. Psychotherapy is an effective approach for alleviating the symptoms associated with emotional disorder, but the number of experienced therapists is low. Studies should be conducted to explore a low-cost and efficient treatment method. Previous findings indicate that transdiagnostic cognitive behavior therapy is an effective approach for treatment of emotional disorders. Group therapy is appropriate for the elderly as they are characterized by high levels of loneliness. In this study, we compared and explored the effects of a transdiagnostic group cognitive behavioral intervention (TD-GCBT), a transdiagnostic individual cognitive behavioral intervention (TD-CBT), and treatment as usual (TAU) on treatment of emotional disorders among the elderly. METHOD: A total of 120 elderly patients diagnosed with emotional disorders were randomly assigned to the TD-GCBT group (40), TD-CBT group (40), and TAU group (40). Changes in symptoms were assessed using HAMD, PHQ-9, HAMA, and GAD-7 scales at baseline, post-treatment (three months), six-month and twelve-months follow-up. The efficacies of the three intervention strategies were compared using linear mixed-effects models. and simple effect analyses were conducted to determine the differences among the three groups. RESULTS: The HAMD, PHQ-9, HAMA, and GAD-7 scores revealed a significant effect from baseline to 12 months for time ( < 0.001), group ( < 0.001) and time × group interaction ( < 0.001) in TD-GCBT group compared with the TD-CBT group and TAU group. The effect of TD-GCBT (HAMD: Cohen's (3th month, 6th month, 12th month) = 2.69, 3.98, 4.51; HAMA: Cohen's = 2.84, 4.13, 5.20) and TD-CBT (HAMD: Cohen's = 2.55, 2.87, 2.63; HAMA: Cohen's = 2.43, 2.83, 2.78) group was better relative to that of the TAU group (HAMD: Cohen's = 0.41, 1.13, 1.46; HAMA: Cohen's = 0.64, 1.22, 1.57) ( < 0.001). The scores of the TD-GCBT group showed the most significant decrease compared with the other two groups. CONCLUSION: The findings indicate that TD-GCBT method is effective for treatment of emotional disorders among the elderly. TD-GCBT is effective for alleviating depression and anxiety symptoms up to at least nine months after treatment. The results indicate that TD-GCBT is a cost-effective and resource-effective strategy and can be used an alternative therapy for treatment of mental disorders. CLINICAL TRIAL REGISTRATION: [https://www.chictr.org.cn], identifier [ChiCTR1900021806].

26Intravenous trazodone for the treatment of psychomotor agitation and associated symptoms in major depressive disorder patients experiencing a depressive episode with mixed features.PubMed

Pietro Carmellini, Alessandro Cuomo, Caterina Pierini, et al.
Int Clin Psychopharmacol. 2025 Jan 13. doi: 10.1097/YIC.0000000000000580.
Psychomotor agitation is a challenging symptom of major depressive disorder with mixed features (MDD-MF), often worsening outcomes and complicating treatment. This retrospective study assessed the efficacy and tolerability of intravenous trazodone in 97 hospitalized patients with MDE-MF. Symptom severity was evaluated using montgomery asberg depression rating Scale (MADRS), young mania rating scale, hamilton anxiety rating scale, GAD-7, and clinical global impression scale-severity of illness (CGI-S) scales, with significant reductions in agitation, anxiety, and irritability observed early during treatment. Correlation analyses revealed significant negative associations between intravenous (IV) trazodone dosage and improvements in MADRS (r = -0.23; P < 0.05), item 5 of GAD-7 (r = -0.27; P < 0.001), and CGI-S scores (r = -0.22; P < 0.05). Therapy duration also correlated negatively with improvements in GAD-7 item 5 (r = -0.29; P < 0.001) and CGI-S (r = -0.27; P < 0.001), indicating diminishing returns with prolonged treatment. Regression analyses showed that therapy duration, but not dosage, significantly influenced improvements in GAD-7 item 5 and CGI-S. Trazodone was well-tolerated, with only mild side effects in 11.3% of patients. These findings suggest that IV trazodone effectively reduces agitation and related symptoms in MDD-MF, particularly in the early treatment phase, emphasizing the importance of optimizing treatment duration. Future studies should investigate individualized dosing strategies and explore long-term outcomes in this population.

27Clinical efficacy of escitalopram combined with botulinum toxin A in patients with generalized anxiety disorder and comorbid headache.PubMed

Yao Wang, Xiaoyu Yang, Xiaojun Ji, et al.
Psychopharmacology (Berl). 2023 Oct;240(10):2061-2070. doi: 10.1007/s00213-023-06423-6. Epub 2023 Jul 22.
BACKGROUND: Generalized anxiety disorder (GAD) is a common mental disorder that happens comorbidly with other diseases. Headache is a common anxiety comorbidity. Previous reports have shown that the selection of therapeutic drugs for GAD patients and comorbid headache is challenging. Therefore, our study aimed to investigate the clinical efficacy of escitalopram combined with botulinum toxin A (BoNT/A) in patients with GAD and comorbid headache and seek an alternative treatment strategy for the comorbidity of GAD and headache. METHODS: A prospective, randomized controlled, double-blind study was performed. The eligible GAD patients with comorbid headache were randomly assigned to the BoNT/A group and the placebo group. All the patients were given oral escitalopram therapy (10-20 mg/day) for the whole duration of the study. The BoNT/A group was given local injections of BoNT/A (50 U per person), whereas the placebo group was given local saline (0.9% NaCl) injections at the beginning and 3 months after the experiments. All participants were followed up for 6 months and relevant information was collected at months 0, 1, 2, 3, and 6. Primary outcomes included the following: (1) the Generalized Anxiety Disorder 7 (GAD-7); (2) the Self-rating Anxiety Scale (SAS); (3) the Hamilton Anxiety Rating Scales (HAMA); (4) days with headache per month; (5) visual analogue scale (VAS). RESULTS: A total of 101 patients (the sex ratio of female to male: 3.39:1) were finally included. Compared with the placebo group, the BoNT/A group showed a significant decrease in GAD-7 scores, SAS scores, HAMA scores, days with headache per month, and VAS scores at months 1, 2, 3, and 6 of follow-up (all p < 0.05). The average time to complete remission of anxiety symptoms (HAMA< 7 points) in the BoNT/A group was less than the placebo group (2 months vs. 3 months). At the same time, the results of the survival analysis showed a clear beneficial effect of BoNT/A relative to placebo on the time to remission of anxiety (log-rank test, p < 0.001). Mean daily doses of escitalopram at the sixth month in the BoNT/A group was smaller than the placebo group (12.5 mg vs. 16.04 mg, p < 0.001). The number of patients who relapsed (HAMA total score ≥ 14 points) at 6 months of follow-up in the BoNT/A group was less than the placebo group (2.2% vs. 14.9%, p < 0.05). The rates of response (HAMA subtraction rate ≥ 50%) were 93.8% for the BoNT/A group and 75.5% for the placebo group (p < 0.05), and the rates of remission (HAMA < 7 points) were 87.5% for the BoNT/A group and 64.2% for the placebo group (p < 0.01) at the sixth month. CONCLUSION: The combination of escitalopram with BoNT/A is a significantly effective intervention in improving clinical efficacy and reducing the recurrence in patients with GAD and comorbid headache, and we believe that this approach will be an additional treatment strategy for future treatment of comorbid headache in GAD. Therefore, we recommend that escitalopram combined with BoNT/A should be given as early as possible in GAD patients and comorbid headache.

28Gamma oryzanol impairs alcohol-induced anxiety-like behavior in mice via upregulation of central monoamines associated with Bdnf and Il-1β signaling.PubMed

Salina Akter, Kazi Rasel Uddin, Hiroyuki Sasaki, et al.
Sci Rep. 2020 Jun 30;10(1):10677. doi: 10.1038/s41598-020-67689-w.
Adolescent alcohol exposure may increase anxiety-like behaviors by altering central monoaminergic functions and other important neuronal pathways. The present study was designed to investigate the anxiolytic effect of 0.5% γ-oryzanol (GORZ) and its neurochemical and molecular mechanisms under chronic 10% ethanol consumption. Five-week-old ICR male mice received either control (14% casein, AIN 93 M) or GORZ (14% casein, AIN 93 M + 0.5% GORZ) diets in this study. We showed that GORZ could potentially attenuate alcohol-induced anxiety-like behaviors by significantly improving the main behavioral parameters measured by the elevated plus maze test. Moreover, GORZ treatment significantly restored the alcohol-induced downregulation of 5-hydroxytryptophan and 5-hydroxyindole acetic acid in the hippocampus and improved homovanillic acid levels in the cerebral cortex. Furthermore, a recovery increase in the level of 3-methoxy-4-hydroxyphenylglycol both in the hippocampus and cerebral cortex supported the anxiolytic effect of GORZ. The significant elevation and reduction in the hippocampus of relative mRNA levels of brain-derived neurotrophic factor and interleukin 1β, respectively, also showed the neuroprotective role of GORZ in ethanol-induced anxiety. Altogether, these results suggest that 0.5% GORZ is a promising neuroprotective drug candidate with potential anxiolytic, neurogenic, and anti-neuroinflammatory properties for treating adolescent alcohol exposure.

29[The effects of antidepressant treatment on efficacy of antihypertensive therapy in elderly hypertension].PubMed

Xiao-jun Cai, Xiu-ping Bi, Zhuo Zhao, et al.
Zhonghua Nei Ke Za Zhi. 2006 Aug;45(8):639-41.
OBJECTIVE: To explore the effect of antidepressant treatment on antihypertensive therapy of senile hypertension. METHODS: 138 cases of senile hypertension complicating with depression were studied. 103 senile hypertensive patients without depression in the same period served as controls. The patients were randomly divided into 3 groups as A, B and C for study. 12.5 mg/d hydrochlorothiazide and 30 mg/d release-controlling tablets of nifedipine were orally administrated as basic antihypertensive medication each group. Besides, 20 mg/d fluoxetine was additionally given to groups A and one tablet of almitrine l/d and 20 mg oryzanol 3/d were given to group B. The treatment lasted 12 weeks. RESULTS: In comparison with pre-treatment, the blood pressure at base line in sitting position and the average circadian SBP and DBP monitored with 24-hour ambulatory blood pressure monitoring (ABPM) was remarkably decreased in group A with statistical significance (P < 0.01). These blood pressure parameters in group B were also decreased as compared ith the pretreatment level brt with less statistical significance (P > 0.05). It was also noted tha with the addition of antidepressant fluoxetine, the manifestations of depression ere alleviated as shown by Hamilton depression (HAMD) scale. untoward reactions such as nausea, perspiration and skin rash were noted in a few patients, but none withdrew from the study. CONCLUSIONS: Antidepressant and antianxiety treatment is of benefit to the antihypertensive therapy in senile hypertensive patients with complications of depression and/or anxiety neurosis. Based on the results of this study, it is suggested that routine administration of antidepressants and antianxiety drugs should be carried out in senile hypertensive patients complicating with depression or anxiety.

30Carcinogenicity study of gamma-oryzanol in B6C3F1 mice.PubMed

M Tamagawa, Y Otaki, T Takahashi, et al.
Food Chem Toxicol. 1992 Jan;30(1):49-56. doi: 10.1016/0278-6915(92)90136-9.
The carcinogenic potential of gamma-oryzanol, a drug mainly used for the treatment of hyperlipidaemia, was studied in B6C3F1 mice. Groups of 50 males and 50 females were fed a diet containing 0 (control), 200, 600 or 2000 mg gamma-oryzanol/kg body weight/day for 78 wk. No treatment-related changes were observed in general condition, body weight, food consumption, mortality, organ weight or haematology. Histopathological examinations showed various tumours in all groups, including the control group. In the control and 2000-mg/kg groups, relatively high tumour incidences were observed in the liver of males and in the haematopoietic organs of females. However, there was no statistically significant difference in the incidence of any tumours between the control and the 2000-mg/kg groups. The findings indicate that under the experimental conditions described gamma-oryzanol was not carcinogenic in B6C3F1 mice.

31Carcinogenicity study of gamma-oryzanol in F344 rats.PubMed

M Tamagawa, Y Shimizu, T Takahashi, et al.
Food Chem Toxicol. 1992 Jan;30(1):41-8. doi: 10.1016/0278-6915(92)90135-8.
The carcinogenic potential of gamma-oryzanol, a drug mainly used for the treatment of hyperlipidaemia, was studied in F344 rats. Groups of 50 males and 50 females were fed a diet containing 0 (control), 200, 600 or 2000 mg gamma-oryzanol/kg body weight/day for 2 yr. Although females in the highest dose group (2000 mg/kg body weight) showed a slight decrease in body weight at 104 wk, there were no treatment-related changes in general condition, food consumption, mortality, organ weight or haematology. Histopathological examination showed various tumours in all groups, including the control group. In the control and 2000-mg/kg groups, high tumour incidences were observed in the testes, pituitary and thyroid of males, and in the pituitary, uterus and mammary gland of females; however, there was no significant increase in the incidence of any tumours between the control and the 2000-mg/kg groups. The findings indicate that under the experimental conditions described gamma-oryzanol was not carcinogenic in F344 rats.

32Efficacy of Food Supplement Based on Monacolins, γ-Oryzanol, and γ-Aminobutyric Acid in Mild Dyslipidemia: A Randomized, Double-Blind, Parallel-Armed, Placebo-Controlled Clinical Trial.PubMed

Lorenza Francesca De Lellis, Maria Vittoria Morone, Daniele Giuseppe Buccato, et al.
Nutrients. 2024 Sep 4;16(17):2983. doi: 10.3390/nu16172983.
The risk of cardiovascular disease (CVD) is approximately doubled in subjects with hypercholesterolemia compared to those with normal blood cholesterol levels. Monacolin K (MK), the main active substance in rice fermented by the , acts on cholesterol metabolism. Rice also contains other bioactive compounds such as γ-oryzanol (OZ) and γ-aminobutyric acid (GABA). In a randomized, placebo-controlled, double-blind trial, the efficacy and tolerability of a food supplement (FS) based on an ingredient standardized to contain monacolins (4.5%), OZ, and GABA were evaluated in subjects with mild dyslipidemia. For the duration of the trial, enrolled subjects ( = 44, each group) received the FS or placebo and were instructed to use an isocaloric diet. Compared to the placebo group, after a 3 months of the FS, the mean low-density lipoprotein cholesterol and mean TC values were reduced by 19.3 and 8.3%, respectively, while the mean high-density lipoprotein cholesterol value increased by 29.3%. On average, the subjects shifted from very high to moderate CVD risk. Glucose metabolism and hepatic and renal parameters did not change after the treatment and no adverse events were reported. Guidelines to handle hypercholesterolemia with food supplements in specific clinical settings are needed to better manage mild dyslipidemia.

33Anxiolytic effects of γ-oryzanol in chronically- stressed mice are related to monoamine levels in the brain.PubMed

Salina Akter, Hiroyuki Sasaki, Kazi Rasel Uddin, et al.
Life Sci. 2019 Jan 1;216:119-128. doi: 10.1016/j.lfs.2018.11.042. Epub 2018 Nov 20.
AIMS: The present study was aimed to investigate the anxiolytic effect of γ-oryzanol (GORZ) during chronic restraint stress treatment (CRST), which is a well-documented model of stress-related disorders, like anxiety, and its potential molecular mechanisms. MATERIALS AND METHODS: In this experiment, 5-week-old male ICR mice were used and the concentration of GORZ was fixed at 0.5% in the mouse standard diet (14% casein, AIN 93 M). Mice were immobilized daily for 3 h from ZT 2.5 to 5.5 (ZT0 was designated as light-on time) for 20 consecutive days, followed by behavioral testing, including the open field test (OFT) and elevated plus maze (EPM) test. The concentration of serum corticosterone (CORT) was measured. In addition, the expression of central monoamine neurotransmitters with their metabolites in the hippocampus, cerebral cortex, and amygdala of the brain were examined. KEY FINDINGS: 0.5% GORZ partially blocked stress-induced reduction of body weight gain while stressed mice had significantly lower body weights during the entire experimental period. Further, 0.5% GORZ treatment could significantly improve the main behavioral parameters even in CRST situations. The significant increase in serum CORT levels indicated CRST-induced stress, which was almost unaffected by 0.5% GORZ treatment. Moreover, 0.5% GORZ also supported the anxiolytic mechanism with enhancement of 5-HIAA and NE levels in the amygdala of brain after CRST. SIGNIFICANCE: Taken together, our studies suggested that 0.5% GORZ is a potential therapeutic drug candidate against anxiety under chronic stress conditions.

34Gamma Oryzanol Alleviates High-Fat Diet-Induced Anxiety-Like Behaviors Through Downregulation of Dopamine and Inflammation in the Amygdala of Mice.PubMed

Salina Akter, Kazi Rasel Uddin, Hiroyuki Sasaki, et al.
Front Pharmacol. 2020 Mar 17;11:330. doi: 10.3389/fphar.2020.00330. eCollection 2020.
BACKGROUND: A high-fat diet (HFD) can induce obesity and metabolic disorders that are closely associated with cognitive impairments, and the progression of several psychiatric disorders such as anxiety. We have previously demonstrated the anxiolytic-like effect of Gamma oryzanol (GORZ) in chronic restraint stressed mice. OBJECTIVE: We studied the neurochemical and molecular mechanisms that underlie the preventive effect of GORZ in HFD-induced anxiety-like behaviors, monoaminergic dysfunction, and inflammation. METHODS: Eight-week-old Institute of Cancer (ICR) male mice weighing 33-34 g were divided into the following groups and free-fed for 8 weeks: control (14% casein, AIN 93M); HFD; HFD + GORZ (0.5% GORZ). Body weight gain was checked weekly. The anxiolytic-like effects of GORZ were examined open-field test (OFT) and elevated plus maze (EPM) test. Brain levels of monoamines [5-hydroxy tryptamine (5-HT), dopamine (DA), and norepinephrine (NE)] and their metabolites [5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], proinflammatory cytokines such as tumor necrosis factor-α () mRNA levels, and interleukin 1-β () mRNA levels in the cerebral cortex and amygdala were examined using high-performance liquid chromatography-electrochemical detection (HPLC-ECD), and real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: Mice fed a HFD for eight weeks showed anxiety-like behaviors in association with HFD-induced body weight gain. GORZ potentially blocked HFD-induced anxiety-like behaviors significant improvement of the primary behavioral parameters in behavioral tests, with a minor reduction in HFD-induced body weight gain. Furthermore, GORZ treatment significantly downregulated HFD-induced upregulation of dopamine levels in the brain's amygdala. Significant reduction of the relative mRNA expression of and was also observed in the amygdala of HFD + GORZ mice, compared to HFD mice. CONCLUSIONS: Our findings strongly suggest that 0.5% GORZ exerts anxiolytic-like effects, possibly through downregulation of dopamine, and expression of proinflammatory cytokines and in the case of chronic HFD exposure.

35The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders.PubMed

Katarzyna Socała, Urszula Doboszewska, Aleksandra Szopa, et al.
Pharmacol Res. 2021 Oct;172:105840. doi: 10.1016/j.phrs.2021.105840. Epub 2021 Aug 24.
Emerging evidence indicates that the gut microbiota play a crucial role in the bidirectional communication between the gut and the brain suggesting that the gut microbes may shape neural development, modulate neurotransmission and affect behavior, and thereby contribute to the pathogenesis and/or progression of many neurodevelopmental, neuropsychiatric, and neurological conditions. This review summarizes recent data on the role of microbiota-gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including depression, anxiety, schizophrenia, autism spectrum disorders, Parkinson's disease, migraine, and epilepsy. Also, the involvement of microbiota in gut disorders co-existing with neuropsychiatric conditions is highlighted. We discuss data from both in vivo preclinical experiments and clinical reports including: (1) studies in germ-free animals, (2) studies exploring the gut microbiota composition in animal models of diseases or in humans, (3) studies evaluating the effects of probiotic, prebiotic or antibiotic treatment as well as (4) the effects of fecal microbiota transplantation.

36Gut microbiome-brain-cirrhosis axis.PubMed

Maren L Smith, James B Wade, Jennifer Wolstenholme, et al.
Hepatology. 2024 Aug 1;80(2):465-485. doi: 10.1097/HEP.0000000000000344. Epub 2023 Mar 6.
Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.

37Gut microbiota modulates neurotransmitter and gut-brain signaling.PubMed

Shiyan Qu, Zijin Yu, Yaxuan Zhou, et al.
Microbiol Res. 2024 Oct;287:127858. doi: 10.1016/j.micres.2024.127858. Epub 2024 Jul 26.
Neurotransmitters, including 5-hydroxytryptamine (5-HT), dopamine (DA), gamma-aminobutyric acid (GABA), and glutamate, are essential transductors in the Gut-Brain Axis (GBA), playing critical roles both peripherally and centrally. Accumulating evidence suggests that the gut microbiota modulates intestinal neurotransmitter metabolism and gut-to-brain signaling, shedding light on the crucial role of the gut microbiota in brain function and the pathogenesis of various neuropsychiatric diseases, such as major depression disorder (MDD), anxiety, addiction and Parkinson's disease (PD). Despite the exciting findings, the mechanisms underlying the modulation of neurotransmitter metabolism and function by the gut microbiota are still being elucidated. In this review, we aim to provide a comprehensive overview of the existing knowledge about the role of the gut microbiota in neurotransmitter metabolism and function in animal and clinical experiments. Moreover, we will discuss the potential mechanisms through which gut microbiota-derived neurotransmitters contribute to the pathogenesis of neuropsychiatric diseases, thus highlighting a novel therapeutic target for these conditions.

38Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.PubMed

Yuanyuan Deng, Manfei Zhou, Junfeng Wang, et al.
Gut Microbes. 2021 Jan-Dec;13(1):1-16. doi: 10.1080/19490976.2020.1869501.
Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, kynurenine (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to "leak" into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed between and Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile, treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior.