唐卓君 綜述 鄒 偉 審校

抑郁癥已經(jīng)成為一種高發(fā)病率和高死亡率的疾病，預(yù)計在2020年將會成為影響人類健康的第二類疾病[1]。抑郁癥是遺傳和環(huán)境因素共同引起的，機制可能是誘發(fā)中樞5-羥色胺 (5-HT) 或去甲腎上腺素 (NE)、多巴胺 (DA) 和神經(jīng)肽等神經(jīng)遞質(zhì)含量降低及其受體功能下降有關(guān)，近年來還有發(fā)現(xiàn)可能與下丘腦-垂體-腎上腺軸負(fù)反饋失調(diào)[2]、谷氨酸傳導(dǎo)障礙[3]、神經(jīng)免疫異常[4]等因素有關(guān)。目前對抗抑郁藥物研究主要集中在闡明生物學(xué)改變機制方面，這些研究成果也很大程度地促進(jìn)了新藥的研發(fā)。

1 選擇性五羥色胺再攝取抑制藥(Selective Serotonin Reuptake Inhibitor，SSRIs)

SSRIs類抗抑郁藥藥理機制主要是抑制神經(jīng)突觸再吸收五羥色胺(5-HT)以提高細(xì)胞外神經(jīng)后突觸與五羥色胺結(jié)合水平從而發(fā)揮藥效。目前常用的SSRIs類藥物主要是氟西汀、帕羅西汀、舍曲林等。這類藥物是臨床常用到的一類抗抑郁藥[5-6]。5-HT為重要的神經(jīng)遞質(zhì)，參與多種生理功能及病理狀態(tài)的調(diào)節(jié)，如睡眠、攝食、體溫、精神情感調(diào)節(jié)。研究發(fā)現(xiàn)抑郁癥患者5-HT水平的降低能影響情感水平[7]，SSRIs主要是通過提升5-HT水平來達(dá)到抗抑郁效果的。SSRIs在臨床上發(fā)揮藥效往往需要幾周的時間，而5-HT水平在運用這類藥物的時候就會出現(xiàn)提高，這種延遲作用暗示這類抗抑郁藥可引起復(fù)雜下游調(diào)控機制改變[8]，如基因調(diào)控改變[1,9]、神經(jīng)回路改變[10]，信號通路改變[11-12]。

2 三環(huán)類抗抑郁藥(tricyclic antidepressants, TCAs)

三環(huán)類抗抑郁藥理機制與SSRIs類相似，主要也是通過阻斷胺泵、減少突觸前膜對生物胺的回收，特別是減少去甲腎上腺素(NE)和5-HT的再吸收，使突觸后受體部位有效神經(jīng)遞質(zhì)的濃度增高，起到抗抑郁作用。常用藥物有丙咪嗪、阿米替林、氯丙咪嗪等。有研究證明SSRIs類和TCAs類抗在臨床藥效抗抑郁的機制都很相似，但SSRIs類抗抑郁藥服藥的依從性較好。近期也研究證明TCAs類抗抑郁藥也能通過激活興奮性突觸改變神經(jīng)細(xì)胞的可塑性從而達(dá)到抗抑郁的作用[13]。

3 單胺氧化酶抑制劑(monoamine oxidase inhibitor, MAOI)

有實驗證實MAOI可逆轉(zhuǎn)利血平引起的淡漠，腦單胺含量卻升高，推測其中樞興奮和抗抑郁作用是因為大腦單胺氧化酶受抑制單胺降解減少及突解間隙單胺類受體含量升高的緣故。這類藥物包括異丙肼、異卡波肼、苯乙肼、反苯環(huán)丙胺，目前對此類藥物研究很少見，主要原因其嚴(yán)重的不良反應(yīng)，所以逐漸停用。但有研究報道MAOI如經(jīng)皮膚吸收不會引起很大副作用，小劑量運用不會引起厭食[14]。此類新開發(fā)藥物，如TV327，在抑郁模型上已證明能夠降低強迫游泳實驗的不動時間[15]。

4 去甲腎上腺素再攝取抑制劑(NRI)

抑郁癥患者體內(nèi)存在去甲腎上腺合成不足和釋放減少，從而導(dǎo)致NE缺乏，去甲腎上腺素再攝取抑制劑主要是增加突觸前膜對去甲腎上腺素的再吸收，增加中樞神經(jīng)系統(tǒng)對去甲腎上腺素再吸收的功能從而發(fā)揮抗抑郁作用，這類藥物包括去甲丙咪嗪、馬普替林和去甲替林，由于其存在抗膽堿能的作用，臨床運用較局限，故此類藥物的研究主要集中在選擇性比較高的藥物，如瑞博西寧(reboxetine)，瑞博西寧能有效降低抑郁癥的發(fā)病率，也能明顯降低NRI類藥物引起的并發(fā)癥[16]。

5 新型抗抑郁藥

雖然目前抗抑郁藥的研究主要集中在SSRIs和TCAs類抗抑郁藥，但也不乏出現(xiàn)了新型抗抑郁藥的研究，如纖維生長因子(Fibroblast Growth Factor-2，F(xiàn)GF-2)，F(xiàn)GF-2能夠降低慢性不可預(yù)知性應(yīng)激(Chonic unpredictable stress, CUS)模型的在強迫游泳中的不動時間，而這可能是通過增加前額去星形膠質(zhì)細(xì)胞來實現(xiàn)的[17-18]。同時也有研究發(fā)現(xiàn)，硫化氫也能改善抑郁及焦慮癥狀，而其可能的機制也在繼續(xù)探究中[19]。

隨著社會壓力的增大，由于抑郁癥引起的自殺人數(shù)是增長趨勢的，醫(yī)藥系統(tǒng)對抑郁癥治療投入的資金越來越多，但是收效甚微，主要原因是對抑郁癥的發(fā)病機制及生物學(xué)改變未完全闡明，抗抑郁藥的作用也是不盡人意，所以如果能對抑郁癥引起機體的潛在改變能做更深入的研究，將會促進(jìn)抗抑郁藥開發(fā)，從而降低抑郁癥的高發(fā)病率和高死亡率。

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