抑郁障碍与嗅觉功能异常

Depressive disorders and olfactory dysfunction

摘要

抑郁障碍是一种具有较高流行率的精神障碍，不仅给患者及其家庭带来沉重的心理压力，也对社会造成显著的经济负担。抑郁障碍与嗅觉功能异常之间存在密切联系，且抑郁障碍常伴随严重的社会功能损害。患者在嗅觉灵敏度、识别、辨别及记忆等多个维度的嗅觉加工过程中均表现出功能异常，这些异常受到症状严重程度及疾病阶段等因素的影响。抑郁障碍患者存在嗅球体积减小、嗅觉皮层结构及功能异常，以及情绪相关脑区(如杏仁核)的结构和功能连接改变。这些神经层面的异常不仅与嗅觉功能障碍相关，也与抑郁症状密切相关，从而为理解抑郁障碍所伴随的情绪与社会功能损伤提供了神经生物学基础。抑郁障碍相关的嗅觉功能异常主要表现为嗅觉灵敏度下降和嗅觉识别能力受损，且常伴随社交退缩等社会功能减退现象。嗅球体积的减小，杏仁核等情绪脑区的结构和功能连接异常，加之神经内分泌失衡和炎症反应增强等病理生理改变，可能共同构成了嗅觉损伤与抑郁症状之间的关键桥梁。基于嗅觉通路的干预手段，如嗅觉训练和吸入式芳香疗法，在一定程度上能够改善患者的嗅觉功能并缓解抑郁症状。这为抑郁障碍的早期识别、诊断及针对嗅觉通路的干预策略提供了理论依据与研究方向。

Abstract

Depressive disorder is a highly prevalent psychiatric condition that imposes substantial psychological burden on patients and their families, as well as significant economic costs to society. A close relationship exists between depressive disorders and abnormalities in olfactory function, and depressive disorders are frequently accompanied by marked impairments in social functioning. Patients exhibit dysfunction across multiple dimensions of olfactory processing, including olfactory sensitivity, identification, discrimination, and memory, and these abnormalities are influenced by symptom severity and stage of illness. Individuals with depressive disorder show reduced olfactory bulb volume, structural and functional abnormalities in the olfactory cortex, and altered structural and functional connectivity in emotion-related brain regions, such as the amygdala. These neural alterations are associated not only with olfactory dysfunction but also closely with depressive symptoms, providing a neurobiological basis for understanding the emotional and social deficits accompanying depressive disorders. Olfactory dysfunction associated with depressive disorders is characterized by reduced olfactory sensitivity and impaired odor identification, often accompanied by social withdrawal and other forms of diminished social functioning. Reduced olfactory bulb volume, abnormalities in the structure and functional connectivity of emotion-related regions such as the amygdala, along with neuroendocrine dysregulation and heightened inflammatory responses, may together constitute the key mechanisms linking olfactory impairment and depressive symptoms. Interventions targeting the olfactory pathway, such as olfactory training and inhalation-based aromatherapy, have been shown to improve olfactory function and alleviate depressive symptoms to some extent. This mechanistic framework provides important theoretical support and research directions for early identification, diagnosis, and olfactory pathway-targeted intervention strategies for depressive disorders.

关键词

抑郁障碍 / 嗅觉功能异常 / 社会功能 / 嗅觉皮层 / 内化问题

Key words

depressive disorders / olfactory dysfunction / social functioning / olfactory cortex / internalizing problem

抑郁障碍是一种常见的心境障碍，情绪低落、快感缺失等症状是其主要的临床特征，给患者的工作、学习、生活造成严重危害。根据世界卫生组织(World Health Organization，WHO)^[1]统计，全球抑郁障碍患病率约为3.8%，其中成年人比例达5%(女性约为6%，男性约为4%)，约有2.8亿人口患抑郁障碍。由于新型冠状病毒的流行，2020年世界范围内的抑郁障碍患者数量增加了28%，且仍呈现逐年上升趋势^[2]。迄今为止，抑郁障碍的病因尚不完全清晰，生物、心理和社会关系等方面均是造成抑郁障碍的重要因素。越来越多的学者对新型冠状病毒感染造成的抑郁障碍现象产生浓厚兴趣，有学者^[3-4]认为嗅觉功能异常可能是抑郁障碍形成与发展的重要诱因。

研究^[5]表明：嗅觉功能异常的患者更有可能表现出抑郁症状。嗅觉功能异常患者中有轻度及更严重抑郁症状的占比约为三分之一。同时，抑郁障碍患者普遍存在嗅觉功能异常，且其异常程度随抑郁程度的增加而加重^{[4, 6]}。尽管嗅觉功能异常与抑郁障碍存在一定关联，但目前仍尚缺乏对“嗅觉损伤是否为抑郁障碍的独立风险因子”的系统探讨。理清嗅觉功能异常与抑郁障碍之间的潜在联系可以加深对抑郁障碍病因的理解，并以此为突破口探究新的治疗方法。

临床研究^[7]发现：患有抑郁障碍的个体不仅嗅觉功能较差，其社交网络通常也比普通人群显著缩小。这提示嗅觉功能异常与社会功能异常可能存在紧密关联^[8]。本文系统性总结嗅觉功能及其神经解剖结构，抑郁障碍、嗅觉功能异常及其神经机制，以及基于嗅觉进行抑郁障碍干预治疗的最新研究进展。

1 嗅觉功能及其神经解剖结构

嗅觉感知具有特定的神经解剖通路，气味信息最初由鼻腔内嗅觉上皮中基底细胞产生的嗅觉感觉神经元感知，并传递到嗅球的小球层，嗅觉感觉神经元与嗅球神经元形成突触连接。随后僧帽细胞与簇状细胞将嗅觉感觉信息传递到初级嗅觉皮层区域^[9-10]，而后传导到与嗅球间接连接的次级嗅觉皮层，包括眶额皮层、海马体、杏仁核等。

嗅觉功能是一个多维嗅觉加工过程，包括嗅觉灵敏度、嗅觉识别、嗅觉辨别、嗅觉记忆等^[11]。基于心理物理法，多个研究团队分别开发了Sniffin’ Sticks测试、宾夕法尼亚大学气味识别测试和中国嗅觉识别测验用于评估嗅觉功能^[12]。

2 抑郁障碍患者存在嗅觉功能异常

关于抑郁障碍患者的嗅觉功能研究主要聚焦于嗅觉灵敏度、嗅觉识别、嗅觉辨别和嗅觉记忆等多个维度，但数量仍然有限。抑郁障碍患者在多维嗅觉加工过程中存在一定程度的功能异常，但不同研究之间结论差异较大，呈现出较高的异质性(附表1，https://doi.org/10.57760/sciencedb.xbyxb.00111)。这说明抑郁相关的嗅觉损伤并非单一、稳定的缺陷，而是受到症状特征、疾病阶段和测量工具等多重因素的共同影响。

2.1 嗅觉灵敏度

抑郁障碍患者的嗅觉阈限高于健康人群，表现为嗅觉灵敏度减弱^[13]，在未接受抗抑郁药物治疗的患者中同样可以观察到这一现象^{[5, 14]}。这提示嗅觉阈值的升高并非单纯由药物所致。与此同时，有研究^[15-16]未发现抑郁障碍组与健康对照组的嗅觉灵敏度存在显著差异，甚至在季节性情感障碍样本中观察到嗅觉灵敏度反而高于对照组。这表明嗅觉灵敏度减弱更可能是部分抑郁障碍患者在特定阶段和表型下的易感或伴随特征，而非所有患者普遍稳定的功能标志，其临床指示意义仍有待在疾病亚型及评估方式得到充分控制的条件下进行进一步检验。

2.2 嗅觉识别

抑郁障碍患者的嗅觉识别能力低于健康人群，且在急性发作期表现更为突出。例如，Wang等^[17]采用中国嗅觉识别测验发现：住院抑郁障碍患者在急性期的嗅觉识别得分显著低于健康对照，而该差异在症状缓解后明显减弱。重度抑郁或晚发型抑郁患者在嗅觉识别任务中的损伤更为明显^[18-19]。然而，多项研究^{[13, 20-27]}均未发现抑郁障碍组与健康对照组之间存在显著差异，整体结果不一致(附表1，https://doi.org/10.57760/sciencedb.xbyxb.00111)，嗅觉识别受损似乎更容易出现在症状较重、处于急性发作期或特定亚型的抑郁障碍患者中，其作为抑郁障碍表征指标的特异性与稳定性，尚缺乏在分层设计和纵向随访框架下的系统验证。

2.3 嗅觉辨别和嗅觉记忆

Croy等^[20]采用Sniffin’ Sticks测试发现：抑郁障碍急性期患者在嗅觉辨别任务中的正确率低于健康对照，治疗后辨别能力随症状缓解而改善。这提示嗅觉辨别可能对抑郁状态变化较为敏感。但更多研究^{[5, 13, 16, 24, 27-29]}并未发现抑郁障碍患者在嗅觉辨别方面存在明显损伤。有研究^[18]比较了重度、轻度抑郁患者与健康对照的差异，结果显示：重度抑郁患者在气味再认准确率和嗅觉记忆得分上显著低于轻度抑郁患者和健康对照，而轻度抑郁患者与健康对照之间的差异并不显著。总体而言，嗅觉辨别和嗅觉记忆的异常目前仍处于探索阶段，更适合作为检验重度或特定表型抑郁障碍亚群的候选指标，而不宜过早被视为抑郁障碍普遍存在的功能缺陷。

综上所述，关于抑郁障碍患者的嗅觉功能异常尚难形成统一结论。一方面，抑郁障碍是一种典型的状态性精神障碍，嗅觉灵敏度和识别等功能往往随症状严重程度和疾病阶段发生波动。例如，研究^[19]发现：急性发作期患者的嗅觉识别减弱，而缓解期表现接近健康水平。另一方面，不同研究^[21-29]在嗅觉测验工具、诊断标准、样本年龄、病程长短等方面均存在差异。未来需要在统一嗅觉评估工具、明确样本分层和疾病阶段的前提下，从多个研究尺度，包括嗅觉加工的生理反应、神经环路结构与功能、神经生物学指标等方面进行更为细致的探索。

3 嗅觉功能异常与社会功能损伤

除部分嗅觉功能异常外，抑郁障碍患者的社会功能也存在一定损伤，嗅觉在其中可能构成重要环节。研究^[30-31]表明：嗅觉功能与社会功能及社交网络之间存在紧密关联(附表2，https://doi.org/10. 57760/sciencedb.xbyxb.00111)。Zou等^[30]的研究发现：个体嗅觉灵敏度越高，其社交网络规模越大，并在杏仁核-眶额皮层功能连接中观察到与嗅觉阈值和社交网络大小相关的共同神经基础。在首发精神病样本中，Etyemez等^[31]的研究发现：嗅觉辨别能力与社会认知能力(如面孔加工)显著相关，提出嗅觉测验有望作为高通量工具，在精神障碍的早期阶段预测社会认知缺陷或功能退化等复杂的临床维度。另有研究^[32-34]从脑结构与功能层面进一步指出：嗅觉加工与社会认知在额叶、颞叶等区域存在重叠，嗅觉识别能力下降可能与社会认知障碍共享部分神经基础。在精神分裂症和双相情感障碍人群中，嗅觉异常与社会功能下降之间的联系也逐渐受到关注，但针对抑郁障碍直接考察嗅觉与社会功能关系的研究仍然匮乏^[35-36]。

抑郁障碍患者的嗅觉灵敏度普遍较低^[37-39]。这可能削弱其对社会性化学信号的感知，使个体难以及时捕捉他人气味和情绪线索，从而不利于社交关系和社会网络的建立与维持。由此可以初步将嗅觉功能异常视为连接抑郁情绪症状与社会功能受损的一条潜在通路，也为后续整合嗅觉指标、社会功能评估和神经影像结果提供了可操作的切入点。

4 抑郁障碍与嗅觉功能异常的神经基础

Deems等^[40]的研究发现750例嗅觉功能异常患者中有25%报告了轻至重度抑郁症状。这表明嗅觉功能异常与抑郁障碍之间可能存在共同的病理心理特征。以往研究^[41-44]提示：嗅觉加工与情绪加工在多个大脑结构与功能上有重叠，其中，嗅觉灵敏度主要和初级嗅觉皮层(如嗅球、梨状皮层)神经功能相关，嗅觉识别与辨别主要与次级嗅觉中枢(如眶额皮层)功能有关，而其他次级嗅觉中枢(如杏仁核与海马体)主要参与嗅觉记忆的加工过程。一项日本的大样本研究^[41]发现嗅觉功能评分与双侧海马体灰质体积显著正相关。这提示海马体可能参与个体的嗅觉加工和记忆维持过程。并且，研究^[45]发现抑郁障碍患者的海马体、杏仁核灰质体积也出现显著降低。静息态功能成像研究^[46]发现：嗅觉功能异常患者与健康对照相比，岛叶皮层和前扣带回/额叶皮层水平的簇内静息态功能连接降低。陈盼等^[47]的研究也表明：与健康对照相比，抑郁障碍患者左侧岛叶前部与双侧前扣带回之间功能连接降低。

嗅球结构的变化在抑郁障碍与嗅觉功能异常之间的联系中至关重要。嗅球是嗅觉初级中枢的一部分，其体积大小与嗅觉功能密切相关。通过神经纤维投射，人类嗅球与杏仁核、丘脑、海马和眶额区皮质等形成广泛的双向联系，该区域同时参与大脑对情绪的产生与调节过程^[48-49]。因此，嗅球被认为是边缘系统的重要组成部分，不仅参与嗅觉功能，同时也参与情绪和记忆过程^[50]。在啮齿类动物模型中，双侧嗅球损伤会引发类似抑郁症的行为表现，并伴随单胺类神经递质系统的紊乱^[51-52]。对抑郁症患者而言，嗅球的缺失或损坏不仅会影响抑郁情绪的形成，而且嗅球体积大小也与抑郁症状的严重程度相关^[53-54]。因此，嗅球体积的减小可能导致嗅觉信息输入的减少，进而增加患抑郁障碍的风险。一些研究者^[55-56]认为这种影响可能与杏仁核在情绪处理中的重要作用相关。杏仁核在情绪处理中扮演关键角色，在大多数抑郁症患者中其功能可能受损。作为嗅觉的主要传递中心，嗅球主要与杏仁核等情绪相关脑区相连。嗅球体积的减小可能导致嗅觉输入减少，进而引起杏仁核功能的改变，并诱发或加剧抑郁症状^[57]。

在此基础上，研究者进一步关注嗅球是否也参与调节情绪相关的神经递质代谢。动物研究^[58]表明：在慢性轻度应激模型小鼠中，嗅球区域的色氨酸羟化酶2表达显著上调，而芳香族氨基酸脱羧酶水平未见显著变化。这提示该区域的5-羟色胺合成通路可能受到应激影响，进而参与抑郁样行为的发生。并且，Singh等^[59]在正电子发射断层显像(positron emission tomography，PET)研究中发现，抑郁患者在多个边缘系统脑区(如杏仁核、海马和内嗅皮层)中均表现出 5-羟色胺系统的功能异常。这些区域不仅参与情绪调节，也是嗅觉信息的次级加工结构，与动物模型中观察到的嗅球区域血清素代谢紊乱在功能层面形成一定的跨物种对应。尽管目前针对嗅球的在体分子成像证据较少，但上述初步证据提示嗅觉通路可能通过神经递质代谢和与情绪脑区的连接，参与情绪障碍的发生。

嗅球切除(olfactory bulbectomy，OBx)小鼠表现出依赖海马体的认知功能障碍(Y迷宫任务中的空间工作记忆损伤和被动回避任务中的学习记忆障碍)，并伴随齿状回区细胞增殖减少；当向背侧海马注射脑源性神经营养因子后，这些神经可塑性损伤和认知缺陷得到显著改善^[60]。考虑到OBx是经典的抑郁动物模型，该研究间接支持了嗅球损伤可能通过影响海马功能，进而干扰认知与情绪加工过程的神经机制路径。

综上所述，尽管已有研究从结构、代谢和网络连接等不同层面初步揭示了嗅球可能在情绪调节中发挥作用，但其在抑郁障碍发生机制中的具体路径仍不清晰。未来研究还可以从神经免疫学视角切入，关注促炎性细胞因子在嗅球区域的表达变化及其对神经元功能的调控作用，进一步探讨炎症是否在嗅觉损伤与抑郁症状之间发挥中介作用。并且，可以引入人工智能方法，尤其是深度学习和大语言模型，结合嗅觉行为数据、神经影像特征和主观报告信息，构建多模态预测模型，探索嗅球变化是否通过调节边缘系统的神经活动，进而增加抑郁症的发生风险。

5 基于嗅觉干预抑郁障碍

Wang等^[17]的研究表明：抑郁障碍患者的嗅觉识别功能异常可以通过抑郁障碍的药物治疗或心理治疗得到缓解。这说明嗅觉功能异常可以作为抑郁症状的标志和一种预测指标，嗅觉系统恢复正常则可以作为疾病良好预后的标志。在抑郁障碍的治疗中，有研究者^[61]开始借助嗅觉感知的训练改善抑郁症状。这种嗅觉训练通过让抑郁患者主动反复嗅闻不同种类的气味物质，刺激患者的嗅觉神经元，改善嗅觉功能。Birte-Antina等^[62]发现轻度抑郁及以上的参与者进行嗅觉训练后，抑郁症状得到明显改善。

此外，研究^[63-72]表明借助吸入式芳香疗法可以改善抑郁症状(附表3，https://doi.org/10.57760/sciencedb. xbyxb.00111)。不同气味类型的精油，如薰衣草精油、玫瑰精油与佛手柑精油等可以作为芳香疗法的训练材料。例如，在Jokar等^[64]的研究中，芳香治疗组中的绝经后妇女连续2周每晚睡前用2%薰衣草精油进行20 min的吸入芳香治疗，与对照组比较，治疗后芳香治疗组患者的抑郁症状水平表现出明显的缓解。目前对吸入式芳香疗法的作用机制尚不清楚，研究^[65-66]表明其可能与嗅觉皮层与血清素的交互作用有关。吸入的精油刺激鼻上皮中与嗅球相连的嗅觉受体细胞后，信号通过嗅球和嗅束传递到大脑中的边缘系统和下丘脑。一旦信号到达，嗅觉皮层就会释放血清素等神经递质，从而对抑郁情绪产生影响。

6 结语与展望

抑郁障碍患者不同维度的嗅觉加工水平可能存在不同程度的异常，从而造成抑郁症状的形成和发展^[73]。然而，由于研究的数量较少、测量工具与研究对象也不统一，抑郁障碍相关嗅觉功能的研究结果存在较高的异质性，这可能与不同嗅觉测试工具的侧重面、抑郁障碍的诊断标准、研究人群的年龄或性别特征及参与的抑郁障碍组之间的严重程度的差异等有关^[74-76]。此外，目前绝大部分关于嗅觉功能与抑郁症状的研究为横断研究，只有少数研究借助纵向追踪设计探索二者的预测关系。例如，Eliyan等^[77]的研究发现：在健康老年人中，基线时嗅觉功能障碍的患者更有可能在5年或10年的随访中出现频繁的抑郁症状，而无论参与者健康状况如何，基线时存在频繁的抑郁症状并不会导致研究参与者5年或10年随访时发生嗅觉功能异常的可能性提高。这需要未来更多的纵向研究进一步探索。

在神经机制方面，目前对抑郁障碍患者嗅觉初级皮层中的前嗅核、梨状皮层与嗅结节等结构的研究较少，且由于对抑郁障碍的认知神经机制的研究还存在着较强的异质性，抑郁障碍中杏仁核、海马体、扣带回和眶额叶皮层等关键区域的结构是否发生改变还未得到一致的定论。未来可以深入探究抑郁障碍患者初级嗅觉皮层中的前嗅核、梨状皮层与嗅结节等结构，以及进一步探究次级嗅觉皮层中的关键结构(如杏仁核、海马体和眶额叶皮层等)是否存在异常，从而探究抑郁障碍与嗅觉功能异常的神经基础是否存在共同关联。未来研究还可从分子影像学与神经免疫学角度出发，进一步揭示嗅觉功能受损在中枢神经系统中的多层级影响机制。与此同时，结合深度学习等人工智能方法，对嗅觉行为、主观体验和神经影像数据进行建模，在多维度上评估嗅觉损伤对情绪状态的预测效能。

关于基于嗅觉通道的抑郁干预，目前已经开发了一些重复的嗅觉训练与吸入式芳香疗法等方法，其相对抗抑郁药物拥有更小的不良反应，且有助于避免头晕、嗜睡、口干、恶心等药物相关不良反应。然而，目前相关研究较少，未来研究可以针对明确诊断为抑郁障碍的患者，进行基于嗅觉通道的抑郁干预。此外，未来可以进一步探究基于嗅觉通道的干预最适宜的气味类型、训练方法与训练频率，以便发挥该方法最优的作用。若能进一步全面地理解抑郁障碍与嗅觉功能异常之间的关系，这可能将有助于抑郁障碍的早期识别、诊断及干预。

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基金资助

上海市卫生健康委员会卫生行业临床研究专项计划(201940491)

教育部人文社会科学青年项目(20YJC190025┫。This work was supported by the Shanghai Municipal Health Commission Health Industry Clinical Research Special Project ┣201940491)

the Youth Project of Humanities and Social Sciences Research Fund, Ministry of Education(20YJC190025)

China.开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(CC BY-NC-ND 4.0┫的方式)

China.开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(在任何媒介以任何形式复制、传播本作品┣https://creativecommons.org/licenses/by-nc-nd/4.0/)

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