重度抑郁癥 (MDD)，俗稱抑郁癥，是一種使人衰弱的疾病，影響全球約3.8%的人口，其中5.0%是成年人，5.7%是60歲以上的人。MDD不同于常見的情緒變化和由于灰質(zhì)和白質(zhì)（包括額葉、海馬體、顳葉、丘腦、紋狀體和杏仁核）的細(xì)微變化而導(dǎo)致的短暫情緒反應(yīng)。如果它以中等或嚴(yán)重的強(qiáng)度發(fā)生，它可能對一個(gè)人的整體健康有害。它會(huì)使一個(gè)人在個(gè)人、職業(yè)和社交生活中表現(xiàn)不佳而痛苦不堪。

一、簡介

重度抑郁癥 (MDD) 被認(rèn)為是最常見的精神疾病，根據(jù)世界衛(wèi)生組織 (WHO) 的說法，它是導(dǎo)致殘疾的主要原因。情緒低落、對日常活動(dòng)的興趣下降、內(nèi)疚、失去快樂、注意力難以集中、自卑、睡眠困難和食欲改變是 MDD 的一些癥狀。

這些問題可能會(huì)長期存在或反復(fù)出現(xiàn)，嚴(yán)重影響一個(gè)人進(jìn)行日常活動(dòng)的能力。在最壞的情況下，抑郁癥會(huì)導(dǎo)致自殺念頭。抑郁癥與患其他嚴(yán)重疾病（如心血管疾病）的幾率增加有關(guān)、中風(fēng)、阿爾茨海默病、癲癇、糖尿病和癌癥。抑郁癥狀在老年人中更常見，但這是由于與衰老相關(guān)的因素造成的，包括身體殘疾、認(rèn)知缺陷、社會(huì)經(jīng)濟(jì)缺陷和其他因素。難治性抑郁癥 (TRD) 可由發(fā)育過程中持續(xù)暴露于環(huán)境壓力源引起。幾乎所有的抗抑郁藥都以相同的方式起作用，并在整個(gè)生命周期內(nèi)有效治療嚴(yán)重的MDD。

然而，抗抑郁治療有許多不良副作用，包括鎮(zhèn)靜、頭痛、血壓下降、失眠、體重增加、消化不良、情緒激動(dòng)、口干、腹瀉和性功能障礙。這通常會(huì)導(dǎo)致患者依從性差，導(dǎo)致抑郁癥狀復(fù)發(fā)和更高的自殺風(fēng)險(xiǎn)。

2. 抑郁癥的神經(jīng)化學(xué)：單胺假說

去甲腎上腺素 (NE)、血清素（5-羥色胺，5HT）和多巴胺 (DA) 失調(diào)與抑郁癥的病理變化有關(guān)（圖1）。根據(jù)抑郁癥的單胺假說，NE、5HT和DA同步發(fā)揮作用，調(diào)節(jié)情緒和情緒。在情緒低落時(shí)，觀察到這三種單胺的失調(diào)，以及細(xì)胞外5HT水平低于平均水平。據(jù)報(bào)道，與年齡匹配的對照組相比，抑郁癥患者的尿液、血液和腦脊液 (CSF) 中的單胺類和代謝物含量較低。

3. 抑郁癥的生長因子

有幾種與抑郁癥狀相關(guān)的生物學(xué)因素，如中所示。與抑郁行為相關(guān)的神經(jīng)回路中的突觸可塑性受腦源性神經(jīng)營養(yǎng)因子(BDNF)調(diào)節(jié)。有趣的是，壓力引起的大腦結(jié)構(gòu)和突觸可塑性損傷可能會(huì)被BDNF上調(diào)逆轉(zhuǎn)，從而導(dǎo)致認(rèn)知的靈活性和適應(yīng)可能刺激抑郁發(fā)作的環(huán)境變化的能力提高。根據(jù)目前的研究，在抑郁癥受試者中，血液中的BDNF水平較低，并且隨著抗抑郁治療的增加而增加，如圖2。研究表明，應(yīng)激誘導(dǎo)的表觀遺傳變化可導(dǎo)致抑郁癥。對MDD顳葉結(jié)構(gòu)研究的兩項(xiàng)薈萃分析表明，復(fù)發(fā)性抑郁癥患者的海馬體較小。此外，無論使用何種藥物，升高的BDNF血漿水平都與更好的治療結(jié)果有關(guān)。

在分子、遺傳、表觀遺傳、細(xì)胞和系統(tǒng)水平上有多種生物學(xué)原因。這些原因會(huì)導(dǎo)致臨床抑郁癥，并且可能會(huì)出現(xiàn)多種癥狀，這些癥狀可能因人而異。

4. 神經(jīng)干細(xì)胞與抑郁癥

近年來，神經(jīng)干細(xì)胞移植引起了人們的興趣，大量發(fā)表的文獻(xiàn)闡明成人大腦維持多能NSCs，這與大腦的舊教條形成鮮明對比，大腦通常是不變的和靜止的器官，缺乏再生的靈活性。憑借其最普遍接受的顯著特征，NSCs也被歸于所謂的組織

干細(xì)胞 ，具有在特定條件下保持未分化而沒有概述表型的能力、分裂和增殖（自我更新）的能力，以及在神經(jīng)發(fā)生開始時(shí)分化成神經(jīng)元、少突膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞等后代的能力。它們是在成年哺乳動(dòng)物大腦的“神經(jīng)源性”區(qū)域（例如海馬體）中發(fā)現(xiàn)的獨(dú)特類型的感受態(tài)細(xì)胞、腦室下區(qū)和神經(jīng)結(jié)構(gòu)，并可能自發(fā)地和響應(yīng)局部信號(hào)感應(yīng)產(chǎn)生神經(jīng)元。神經(jīng)發(fā)生 (NG) 被認(rèn)為需要一組明確的信號(hào)線索，以通過周圍環(huán)境在空間和時(shí)間上非常協(xié)調(diào)的方式傳遞給神經(jīng)源性細(xì)胞，以激活干細(xì)胞或祖細(xì)胞以發(fā)育新的神經(jīng)元，此外，眾所周知的調(diào)制器，損傷被認(rèn)為足以激活神經(jīng)發(fā)生。BDNF 的表達(dá)也會(huì)刺激神經(jīng)發(fā)生。NSC通常是從成人腦組織中提取的，包括死后腦組織，并成為增加或恢復(fù)受中樞神經(jīng)系統(tǒng)相關(guān)疾病影響的腦組織質(zhì)量和功能的重要候選者。NSC在體外進(jìn)行克隆擴(kuò)增、基因操作或刺激以轉(zhuǎn)化CNS細(xì)胞譜系。了解成人神經(jīng)發(fā)生的調(diào)節(jié)方式需要大量工作。 

生長因子、遞質(zhì)、酶、組織激素、神經(jīng)調(diào)節(jié)劑和抗體預(yù)計(jì)會(huì)被激活的細(xì)胞分泌到局部組織環(huán)境中，從而引發(fā)所需的組織反應(yīng)。在受損的神經(jīng)元和神經(jīng)膠質(zhì)網(wǎng)絡(luò)中，新賦能的細(xì)胞及其后代可以作為功能增強(qiáng)劑和支架“修復(fù)劑”發(fā)揮作用。這些特性導(dǎo)致創(chuàng)傷和灌注問題（如中風(fēng) 、局部缺血或神經(jīng)退行性病）療法的發(fā)明取得實(shí)質(zhì)性進(jìn)展。

不出所料，NSCs在精神衛(wèi)生保健方面的前景正在引起激烈爭論。許多精神疾病可能具有遺傳變異以及大多數(shù)未知的特定細(xì)胞和解剖相關(guān)性。

在抑郁癥中，海馬體中經(jīng)常會(huì)出現(xiàn)神經(jīng)發(fā)生減少。這進(jìn)一步意味著神經(jīng)發(fā)生缺陷可能導(dǎo)致與抑郁癥相關(guān)的癥狀，而增強(qiáng)的神經(jīng)發(fā)生可以介導(dǎo)抗抑郁作用并緩解癥狀。

然而，在建立這種雙向概念的完全合法性之前，必須首先調(diào)和關(guān)于神經(jīng)發(fā)生在緩解抑郁癥中的作用的各種相互矛盾的報(bào)告。成人海馬神經(jīng)發(fā)生的激活導(dǎo)致神經(jīng)體細(xì)胞后代轉(zhuǎn)化為成熟的CNS神經(jīng)元。然后，這些中樞神經(jīng)系統(tǒng)神經(jīng)元獲得功能和形態(tài)特性，以整合到現(xiàn)有的神經(jīng)網(wǎng)絡(luò)或替換其他各種已經(jīng)死亡的腦細(xì)胞。

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