本文關(guān)鍵詞：加味柴胡桂枝湯合并文拉法辛治療中重度抑郁癥的回顧性研究，由筆耕文化傳播整理發(fā)布。

        課題背景：抑郁癥通常指的是情感障礙,是一種常見(jiàn)的心境障礙,可由各種原因引起,以顯著而持久的心境低落為主要臨床特征,且心境低落與其處境不相稱,臨床表現(xiàn)可以從悶悶不樂(lè)到悲痛欲絕,甚至發(fā)生木僵；部分病例有明顯的焦慮和運(yùn)動(dòng)性激越；嚴(yán)重者可出現(xiàn)幻覺(jué)、妄想等精神病性癥狀。多數(shù)病例有反復(fù)發(fā)作的傾向,每次發(fā)作大多數(shù)可以緩解,部分可有殘留癥狀或轉(zhuǎn)為慢性。世界衛(wèi)生組織的一項(xiàng)以15個(gè)城市為中心的全球性合作研究,調(diào)查綜合醫(yī)院就診者中的心理障礙,發(fā)現(xiàn)患抑郁癥和惡劣心境者達(dá)12.5%。在10個(gè)國(guó)家和地區(qū)(包括美國(guó)、加拿大、黎巴嫩、韓國(guó)、中國(guó)臺(tái)灣等)的對(duì)38000個(gè)體的社區(qū)調(diào)查,發(fā)現(xiàn)各國(guó)抑郁癥的終生患病率相差懸殊,中國(guó)臺(tái)灣僅為1.5%,而黎巴嫩高達(dá)19.0%；年發(fā)病率在中國(guó)臺(tái)灣為0.8%,美國(guó)新澤西則為5.8%。WHO(1993)的多中心全球合作研究中,上海調(diào)查表明,在綜合醫(yī)院內(nèi)科門診的抑郁癥患病率為4.0%,惡劣心境為0.6%。臺(tái)灣、香港等地華人的抑郁癥患病率也較低,臺(tái)灣人群中抑郁癥終生患病率為1.5%,遠(yuǎn)低于其他亞洲地區(qū)(韓國(guó)2倍于臺(tái)灣地區(qū))。在對(duì)中國(guó)臺(tái)灣老年抑郁癥患者的23項(xiàng)橫斷面的流行病學(xué)調(diào)查資料的綜合分析顯示,抑郁癥的患病率為3.86%,農(nóng)村的抑郁癥發(fā)病危險(xiǎn)率為5.07%,高于城市的2.61%,遠(yuǎn)低于西方國(guó)家的患病率。WHO(1993)的全球疾病負(fù)擔(dān)(GBD)的合作研究表明,全球的神經(jīng)精神疾病負(fù)擔(dān)中抑郁癥、自殺分別為17.3%、15.9%,高居榜首；抑郁癥占傷殘調(diào)整生命年(DALY)減少的4.2%；抑郁癥和自殺占5.9%。提示抑郁癥、自殺/自傷是精神障礙中導(dǎo)致疾病負(fù)擔(dān)損失最大的問(wèn)題,應(yīng)予以重視。研究還預(yù)測(cè),到2020年抑郁癥將成為繼冠心病后的第二大疾病負(fù)擔(dān)源。預(yù)測(cè)從1990-2020年中國(guó)的神經(jīng)精神疾病負(fù)擔(dān)將從14.2%增至15.5%,加上自殺與自傷,將從18.1%升至20.2%,占全部疾病負(fù)擔(dān)的1/5。精神障礙與自殺所占疾病負(fù)擔(dān)將名列第1、2位(20.2%),抑郁癥、自殺與自傷,以及老年癡呆的疾病負(fù)擔(dān)明顯增加,而抑郁癥仍是精神疾病負(fù)擔(dān)中的最主要問(wèn)題(1990年為44%,預(yù)測(cè)2020年將為47%)。抑郁障礙具有高發(fā)病、高復(fù)發(fā)、高致殘的特點(diǎn),所帶來(lái)的后果就是沉重的經(jīng)濟(jì)負(fù)擔(dān),給社會(huì)造成巨大的經(jīng)濟(jì)損失。美國(guó)(1994)總的健康費(fèi)用中4%用于治療抑郁障礙,高達(dá)430億美元；其中僅90億美元(28%)是直接醫(yī)療費(fèi)用,其余340億美元?jiǎng)t是因患者致病或致殘后所造成的各種損失。目前診治的情況不容樂(lè)觀,對(duì)抑郁障礙的總體識(shí)別率較低,尤其是在綜合醫(yī)院。WHO的多中心合作研究顯示,15個(gè)不同國(guó)家或地區(qū)的內(nèi)科醫(yī)生對(duì)抑郁癥的識(shí)別率平均為55.6%,中國(guó)上海的識(shí)別率為21%,遠(yuǎn)遠(yuǎn)低于國(guó)外水平。因此,加強(qiáng)抑郁癥的防治,尋找積極有效的治療方法,具有非常重要的社會(huì)和經(jīng)濟(jì)意義。抑郁癥治療目前主要有藥物治療、心理治療及電驚厥治療等多種方式,而當(dāng)前最為普遍的治療方法仍為抗抑郁藥物治療。相關(guān)資料表明,10%-30%的病人對(duì)于抗抑郁藥的治療反應(yīng)差。除此之外,對(duì)于抗抑郁制劑療法表現(xiàn)出很多負(fù)面作用,如性欲降低、惡心,嘔吐,震顫,尿阻滯,生理失調(diào),肥胖等。以SSRI類及SNRI類為代表的新型抗抑郁藥較傳統(tǒng)抗抑郁藥毒副作用減弱,但作用機(jī)制和三環(huán)類藥物本質(zhì)上一致,只能針對(duì)單一發(fā)病機(jī)制,只能緩解部分癥狀,不足以兼顧多種致病因素,無(wú)法解決抑郁癥多種發(fā)病病因及發(fā)病機(jī)制的問(wèn)題。且其藥效和應(yīng)用范圍并不優(yōu)于傳統(tǒng)藥物,僅50%的患者可以完全解除癥狀。其藥效起效延遲,藥理作用在2-4周時(shí)開(kāi)始發(fā)揮作用,無(wú)法迅速解決患者主訴癥狀。文拉法辛是一種5-羥色胺與去甲腎上腺素再攝取抑制劑,其雙重活性的作用機(jī)制對(duì)抑郁癥的治療效果較選擇性5-羥色胺再攝取抑制劑更有優(yōu)勢(shì),在轉(zhuǎn)換策略上較SSRI有潛在的優(yōu)勢(shì)。在安全性與耐受性方面,納入的試驗(yàn)統(tǒng)計(jì)文拉法辛與SSRI的副反應(yīng)主要是惡心、嘔吐、口干等消化系統(tǒng)癥狀；頭昏、頭痛等神經(jīng)系統(tǒng)癥狀,兩者無(wú)明顯差異。提示文拉法辛是一種具有良好安全性與耐受性的抗抑郁藥。抑郁癥屬中醫(yī)“郁病”范疇,由氣機(jī)郁滯,臟腑功能失調(diào)而至心情抑郁,情緒不寧,胸部滿悶,脅肋脹痛,或易怒欲哭,或咽中有異物感等癥為主要臨床特征。祖國(guó)醫(yī)學(xué)對(duì)郁病的認(rèn)識(shí)由來(lái)已久,傳統(tǒng)中醫(yī)認(rèn)為抑郁癥的病因有內(nèi)外兩個(gè)方面,其外因?yàn)榍橹舅鶄?其內(nèi)因?yàn)榕K氣易郁。其病機(jī)主要為氣機(jī)郁滯,臟腑功能失調(diào)。郁病初起病變以氣滯為主,氣郁日久,則可引起血瘀、化火、痰結(jié)、食滯、濕停等,多屬實(shí)證,日久則易由實(shí)轉(zhuǎn)虛,隨其影響的臟腑及損耗氣血陰陽(yáng)的不同,而形成心、肝、脾、腎虧虛的不同病變。理氣開(kāi)郁、怡情易性是治療的基本原則。加味柴胡桂枝湯是國(guó)家名老中醫(yī)陳寶田教授在多年治療抑郁癥的臨床經(jīng)驗(yàn)的基礎(chǔ)上,參閱古今文獻(xiàn),經(jīng)過(guò)多年潛心研究,針對(duì)抑郁癥肝郁傷神為重要病機(jī),在經(jīng)方柴胡桂枝湯的基礎(chǔ)上擬定的以疏肝理氣、解郁安神,兼以平陰陽(yáng)、調(diào)五神、和營(yíng)衛(wèi)為特點(diǎn)的經(jīng)驗(yàn)方。柴胡桂枝湯具有疏肝理氣、化痰之功,生龍牡和靈磁石能鎮(zhèn)肝、平肝,夜交藤、茯神解郁安神,諸藥合用,達(dá)到疏肝理氣、鎮(zhèn)肝平肝、健脾養(yǎng)心、解郁安神之效。近年來(lái),我們?cè)谂R床上多采用加味柴胡桂枝湯合并文拉法辛的方式對(duì)抑郁癥開(kāi)展治療,獲得了一定的療效。因此,結(jié)合我們對(duì)既往治療的療效觀察,進(jìn)行回顧性分析加味柴胡桂枝湯合并文拉法辛治療中重度抑郁癥的療效。本課題將更多關(guān)注患者服藥后副反應(yīng)的緩解及改善情況,中藥對(duì)降低抗抑郁劑的副作用,緩解抑郁癥的核心癥狀及周邊癥狀的有效性和安全性。目的：通過(guò)對(duì)105例抑郁癥患者的回顧性分析,進(jìn)一步評(píng)價(jià)中西醫(yī)結(jié)合治療抑郁癥的有效性及安全性,尤其是中藥在提高抗抑郁療效及減輕西藥副作用的影響。對(duì)象和方法：1.對(duì)象2010年1月～2011年12月在南方醫(yī)科大學(xué)南方醫(yī)院中醫(yī)科門診、病房及中西醫(yī)結(jié)合醫(yī)院腦病科門診、病房診斷為抑郁癥的患者105例。2.納入及排除標(biāo)準(zhǔn)抑郁癥的診斷標(biāo)準(zhǔn)：均符合中國(guó)精神疾病分類與診斷標(biāo)準(zhǔn)第3版(CCMD-3)抑郁癥診斷標(biāo)準(zhǔn)。納入標(biāo)準(zhǔn)：(1)符合CCMD-3抑郁癥診斷標(biāo)準(zhǔn)的病例；(2)漢密爾頓抑郁量表(HAMD-17)評(píng)分≥17分；(3)性別與種族不限,住院與門診病人不限；(4)年齡>18歲；(5)病程≥30天以上；(6)完善常規(guī)檢查,未見(jiàn)明顯嚴(yán)重器質(zhì)性病變；(7)完成12周治療的患者。排除標(biāo)準(zhǔn)：(1)排除不符合CCMD-3抑郁癥診斷標(biāo)準(zhǔn)的其他精神疾��；(2)出現(xiàn)嚴(yán)重自殺傾向者；(3)年齡<18歲；(4)完善常規(guī)檢查,伴有明顯嚴(yán)重器質(zhì)性病變；(5)孕婦、哺乳期婦女；(6)對(duì)本藥物過(guò)敏者；(7)長(zhǎng)期服用精神類藥物且劑量不穩(wěn)定、單胺氧化酶抑制劑、鋰劑及丙戊酸、卡馬西平等抗癲癇劑；(8)凡不符合納入標(biāo)準(zhǔn),未按規(guī)定服藥,無(wú)法判定療效或資料不全等影響療效和安全性判斷者。3.方法試驗(yàn)方法：回顧性研究。選擇病例標(biāo)準(zhǔn)：包括診斷標(biāo)準(zhǔn)、納入標(biāo)準(zhǔn)及排除標(biāo)準(zhǔn)。其中診斷標(biāo)準(zhǔn)參照中國(guó)精神疾病分類與診斷標(biāo)準(zhǔn)第3版(CCMD-3)抑郁癥診斷標(biāo)準(zhǔn),同時(shí)結(jié)合中醫(yī)辯證標(biāo)準(zhǔn)。治療藥物：治療組給予文拉法辛緩釋片基礎(chǔ)上聯(lián)合加味柴胡桂枝湯(柴胡、半夏、黨參、甘草、黃芩、桂枝、白芍、生姜、大棗、生龍骨、生牡蠣、靈磁石、夜交藤、茯神等)；對(duì)照組單用文拉法辛緩釋片。用藥方法：兩組均給予文拉法辛緩釋片,治療組聯(lián)合中藥加味柴胡桂枝湯。治療周期為12周。合并用藥規(guī)定：用藥期間不得合并使用任何抗精神病藥,抗抑郁藥,心境穩(wěn)定劑等藥物。用藥期間若嚴(yán)重失眠者,可以適當(dāng)合用唑吡坦或阿普唑侖,佐匹克隆和短效苯二氮卓鎮(zhèn)靜藥,如舒樂(lè)安定等。觀測(cè)指標(biāo)：包括人口學(xué)資料、影響療效因素、一般體格檢查及實(shí)驗(yàn)室檢查。療效判定標(biāo)準(zhǔn)：包括抑郁癥療效判定標(biāo)準(zhǔn),治療前后相關(guān)量表分?jǐn)?shù)的變化情況。不良事件的觀察：不良事件的術(shù)語(yǔ)涵蓋了在臨床研究期間,受試者出現(xiàn)并會(huì)影響健康的任何臨床證候、癥狀、綜合征或某種疾病出現(xiàn)或惡化。不良事件可能是：新的疾��；治療狀態(tài)癥狀或體征的惡化,或伴隨疾病的惡化；對(duì)照藥物的作用；與參加該試驗(yàn)無(wú)關(guān)；一個(gè)或多個(gè)因素的組合。所以,“不良事件”這一術(shù)語(yǔ)并不意味著與試驗(yàn)藥物的因果關(guān)系。4.統(tǒng)計(jì)學(xué)處理所有數(shù)據(jù)采用SPSS13.0統(tǒng)計(jì)軟件包進(jìn)行統(tǒng)計(jì)分析。計(jì)量資料作正態(tài)性檢驗(yàn),如樣本符合正態(tài)分布以均數(shù)士標(biāo)準(zhǔn)差(x士SD)表示。服藥前后各時(shí)間點(diǎn)的量表評(píng)分變化數(shù)據(jù)采用重復(fù)測(cè)量方差分析。治療后兩組HAMD減分療效分析采用廣義估計(jì)方程(generalized estimating equations, GEE)。計(jì)數(shù)資料用例數(shù)(%)表示,組間比較采用X2檢驗(yàn)；如數(shù)據(jù)出現(xiàn)理論值<1,則用Fisher確切概率法。等級(jí)資料采用秩和檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果：1HAMD量表評(píng)分變化：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=1204.507,P=0.000),治療組F=295.401、P=0.000,對(duì)照組F=167.256、P=0.000。兩組之間HAMD量表評(píng)分差異有統(tǒng)計(jì)學(xué)意義(F=7.776,P=0.006),從各時(shí)間點(diǎn)看,除基線期HAMD量表評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(t=-0.6)8,P=0.538)外,服藥1周、2周、4周、6周、8周及12周后兩組HAMD量表評(píng)分差異均有統(tǒng)計(jì)學(xué)意義(t值分別為2.654、3.397、3.203、2.840、3.322、3.821,P值分別為0.009、0.001、0.002、0.005、0.001、0.000),表明自患者服藥1周以后的各時(shí)間點(diǎn),抑郁癥患者HAMD量表評(píng)分的降低幅度治療組均優(yōu)于對(duì)照組。兩組與服藥時(shí)間之間存在交互效應(yīng)(F=7.667,P=0.000),與前面不同時(shí)間點(diǎn)兩組之間多重比較結(jié)果分析相吻合,表明兩組抑郁癥患者HAMD量表評(píng)分的變化隨給藥時(shí)間的延長(zhǎng)呈下降趨勢(shì)。2.SDS量表評(píng)分變化：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=2012.564,P=0.000),治療組F=610.854、P=0.000,對(duì)照組F=68.278、P=0.000。兩組之間SDS量表評(píng)分差異有統(tǒng)計(jì)學(xué)意義(F=116.876,P=0.000),從各時(shí)間點(diǎn)看,除基線期SDS量表評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(t=-1.529,P=0.129)外,服藥1周、2周、4周、6周、8周及12周后兩組SDS量表評(píng)分差異均有統(tǒng)計(jì)學(xué)意義(t值分別為3.037、7.126、11.466、16.711、21.326、23.747,P值分別為0.003、0.000、0.000、0.000、0.000、0.000),表明自患者服藥1周以后的各時(shí)間點(diǎn),抑郁癥患者SDS量表評(píng)分的降低幅度治療組均優(yōu)于對(duì)照組。兩組與服藥時(shí)間之間存在交互效應(yīng)(F=258.781,P=0.000),與前面不同時(shí)間點(diǎn)兩組之間多重比較結(jié)果分析相吻合,表明兩組抑郁癥患者SDS量表評(píng)分的變化隨給藥時(shí)間的延長(zhǎng)呈下降趨勢(shì)。3.SAS量表評(píng)分變化：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=1123.184,P=0.000),治療組F=402.742、P=0.000,對(duì)照組F=60.464、P=0.000。兩組之間SAS量表評(píng)分差異有統(tǒng)計(jì)學(xué)意義(F=92.576,P=0.000),從各時(shí)間點(diǎn)看,除基線期SAS量表評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(t=-1.712,P=0.090)外,服藥1周、2周、4周、6周、8周及12周后兩組SAS量表評(píng)分差異均有統(tǒng)計(jì)學(xué)意義(t值分別為2.209、6.873、12.002、17.548、17.172、18.394,P值分別為0.029、0.000、0.000、0.000、0.000、0.000),表明自患者服藥1周以后的各時(shí)間點(diǎn),抑郁癥患者SAS量表評(píng)分的降低幅度治療組均優(yōu)于對(duì)照組。兩組與服藥時(shí)間之間存在交互效應(yīng)(F=150.707,P=0.000),與前面不同時(shí)間點(diǎn)兩組之間多重比較結(jié)果分析相吻合,表明兩組抑郁癥患者SAS量表評(píng)分的變化隨給藥時(shí)間的延長(zhǎng)呈下降趨勢(shì)。4HAMD睡眠障礙分析比較：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=531.498,P=0.000),兩組與服藥時(shí)間之間存在交互效應(yīng)(F=7.657,P=0.000)。治療組F=137.232、P=0.000,對(duì)照組F=72.397、P=0.000。兩組之間睡眠障礙評(píng)分差異有統(tǒng)計(jì)學(xué)意義(F=27.041,P=0.000),從各時(shí)間點(diǎn)看,除基線期睡眠障礙因子評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(t=0.518,P=0.605)外,服藥1周、2周、4周、6周、8周及12周后兩組睡眠障礙評(píng)分差異均有統(tǒng)計(jì)學(xué)意義(t值分別為3.946、5.417、4.636、5.787、5.739、5.357,P值分別為0.000、0.000、0.000、0.000、0.000、0.000),表明治療前兩組患者睡眠障礙評(píng)分處于同一水平,具有可比性。自患者服藥1周以后的各時(shí)間點(diǎn),抑郁癥患者HAMD‘睡眠障礙評(píng)分的降低幅度治療組均優(yōu)于對(duì)照組。5HAMD抑郁和焦慮反應(yīng)分析比較：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=546.509,P=0.000),兩組與服藥時(shí)間之間存在交互效應(yīng)(F=2.911,P<0.008)。治療組F=133.542、P=0.000,對(duì)照組F=79.791、P=0.000。兩組之間抑郁和焦慮反應(yīng)評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(F=2.032,P=0.157),從各時(shí)間點(diǎn)看,基線期及服藥1周、2周、4周、6周抑郁和焦慮反應(yīng)評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(t值分別為-0.658、1.368、1.904、1.573、1.444,P值分別為0.512、0.174、0.060、0.119、0.152),8周及12周后兩組抑郁和焦慮反應(yīng)評(píng)分差異有統(tǒng)計(jì)學(xué)意義(t值分別為2.578、2.125,P值分別為0.011、0.037),表明治療前兩組患者抑郁和焦慮反應(yīng)因子處于同一水平,具有可比性,并且自患者服藥1周、2周、4周、6周內(nèi),兩組抑郁癥患者HAMD抑郁和焦慮反應(yīng)評(píng)分的降低幅度相當(dāng)。但自患者服藥8周及12周后,HAMD抑郁和焦慮反應(yīng)評(píng)分的降低幅度開(kāi)始出現(xiàn)治療組優(yōu)于對(duì)照組。6HAMD情感淡漠分析比較：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=125.812,P=0.000),兩組與服藥時(shí)間之間不存在交互效應(yīng)(F=0.660,P=0.682)。治療組F=27.778、P=0.000,對(duì)照組F=19.172、P=0.000。兩組之間情感淡漠評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(F=0.003,P=0.954),從各時(shí)間點(diǎn)看,基線期及服藥1周、2周、4周、6周、8周、12周后兩組情感淡漠評(píng)分差異均無(wú)統(tǒng)計(jì)學(xué)意義(t值分別為-0.801、0.036、0.343、0.521、-0.037、-0.174、-0.243,P值分別為0.425、0.971、0.732、0.604、0.970、0.862、0.808),表明治療前兩組患者情感淡漠評(píng)分處于同一水平,具有可比性,并且自患者服藥1周以后的各時(shí)間點(diǎn),兩組抑郁癥患者HAMD情感淡漠評(píng)分的降低幅度相當(dāng)。7HAMD軀體癥狀分析比較：給藥前后兩組不同時(shí)間點(diǎn)之間差異均有統(tǒng)計(jì)學(xué)意義(F=421.576,P=0.000),兩組與服藥時(shí)間之間不存在交互效應(yīng)(F=1.675,P=0.125)。治療組F=114.595、P=0.000,對(duì)照組F=96.139、P=0.000。兩組之間軀體癥狀評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(F=0.886,P=0.349),從各時(shí)間點(diǎn)看,基線期及服藥1周、2周、4周、6周、8周、12周后兩組軀體癥狀評(píng)分差異均無(wú)統(tǒng)計(jì)學(xué)意義(t值分別為-0.418、1.447、1.186、1.583、0.904、0.472、0.399,P值分別為0.677、0.151、0.238、0.116、0.368、0.638、0.691),表明治療前兩組患者軀體癥狀因子處于同一水平,具有可比性,并且自患者服藥1周以后的各時(shí)間點(diǎn),兩組抑郁癥患者HAMD軀體癥狀評(píng)分的降低幅度相當(dāng)。8HAMD減分療效分析：治療組和對(duì)照組有顯著差異(Z=3.82,P<0.001),治療組療效優(yōu)于對(duì)照組；不同時(shí)間點(diǎn)間有顯著差異(Z=13.64,P<0.001),隨著時(shí)間的延長(zhǎng),療效愈好；組別和時(shí)間點(diǎn)間沒(méi)有交互效應(yīng)(Z=-0.43,P=0.668)。用藥后1周、2周、4周、6周、8周、12周的各時(shí)間點(diǎn),治療組與對(duì)照組療效級(jí)別秩次分別為：55.63、49.50；61.85、41.20；60.50、43.00；63.21、39.39；58.83、45.22；60.43、43.09。兩組在用藥后的各時(shí)間點(diǎn)差異均有統(tǒng)計(jì)學(xué)意義(Z=-2.360,P=0.018；Z=-3.985,P<0.000；Z=-3.714,P<0.000；Z=-4.403,P<0.000：Z=-2.723,P=0.006；Z=-3.809,P<0.000)。9.起效時(shí)間分析：在治療第1周時(shí),治療組和對(duì)照組在起效時(shí)間上差異有統(tǒng)計(jì)學(xué)意義(X2=16.293,P<0.000),治療組30%患者獲得起效,而對(duì)照組未見(jiàn)明顯起效。而在治療第2周時(shí),治療組和對(duì)照組在起效時(shí)間上差異更顯著(X2=19.604,P<0.000),治療組88.3%患者獲得起效,而對(duì)照組僅48.9%患者獲得起效。10.治療12周末治愈率比較：治療組和對(duì)照組在臨床治愈率比較上差異有統(tǒng)計(jì)學(xué)意義(X2=14.463,P<0.000)。在治療12周末,治療組臨床治愈率為88.3%,而對(duì)照組臨床治愈率僅為55.6%。11.不良反應(yīng)分析：治療組各種不良反應(yīng)發(fā)生率均低于對(duì)照組,兩組在口干(X2=10.423,P<0.001)、便秘(X2=6.099,P=0.014<0.05)及性功能障礙(X2=4.257,P=0.039<0.05)等發(fā)生率上相比差異具有統(tǒng)計(jì)學(xué)意義,治療組在口干、便秘及性功能障礙等發(fā)生率明顯低于對(duì)照組。結(jié)論：1.加味柴胡桂枝湯合并文拉法辛對(duì)抑郁癥及合并焦慮癥的改善作用優(yōu)于單用文拉法辛,而且隨治療時(shí)間的延長(zhǎng),對(duì)抑郁癥及焦慮癥的改善作用可能更穩(wěn)定。2.加味柴胡桂枝湯合并文拉法辛對(duì)睡眠障礙的改善優(yōu)于單用文拉法辛組。而對(duì)抑郁和焦慮反應(yīng)的改善,一直到治療8周后,才出現(xiàn)優(yōu)于單用文拉法辛組,這可能提示隨著治療時(shí)間的延長(zhǎng),改善抑郁和焦慮反應(yīng)的療效會(huì)逐漸明顯。而對(duì)情感淡漠及軀體癥狀的改善,療效表現(xiàn)不明顯。3.加味柴胡桂枝湯合并文拉法辛臨床治愈率為88.3%,而單用文拉法辛組臨床治愈率僅為55.6%。提示加味柴胡桂枝湯聯(lián)合文拉法辛臨床治愈率可能要高于單用文拉法辛。4.加味柴胡桂枝湯合并文拉法辛在第一周出現(xiàn)30%患者獲得起效,治療兩周后,起效達(dá)到88.3%。同時(shí),單用文拉法辛僅在第二周出現(xiàn)48.9%患者獲得起效。提示在起效時(shí)間上要明顯快于單用文拉法辛。5.加味柴胡桂枝湯合并文拉法辛可能在不同程度上減輕文拉法辛的副作用,尤其在減輕口干、便秘及性功能障礙等不良反應(yīng)上表現(xiàn)可能更顯著。

    Research background:Depression usually refers to affective disorder is a common mood disorder can be caused by a variety of reasons, significantly low long-lasting state of mind as the main clinical features, and the depressed state of mind and its not commensurate with the situation, clinical manifestations can be depressed to griefstricken, and even stupor; in some cases there is significant anxiety and agitation; severe cases, hallucinations, delusions and other psychotic symptoms. Most cases have a tendency to recurrent episodes of most of each attack can be alleviated, some may have residual symptoms or become chronic.World Health Organization of one to15cities as the center of global collaborative research to investigate the psychological barrier in the hospital who found suffering from depression and dysthymia of12.5%. Community survey of38,000individuals in10countries and regions (including the United States, Canada, Lebanon, Korea, China Taiwan) and found that the lifetime prevalence rate of the national depression disparities, China Taiwan only.5%up to19.0%in Lebanon; annual incidence in China Taiwan is0.8%, New Jersey, compared with5.8percent. WHO (1993), multi-center study of global cooperation, the Shanghai survey showed that the prevalence rate of4.0%in the general hospital medical outpatient depression, dysthymia0.6%. Chinese in Taiwan, Hong Kong, the prevalence of depression is low, the population of Taiwan depression lifetime prevalence rate of1.5%, much lower than other regions in Asia (South Korea2times in Taiwan). Shown in the comprehensive analysis of epidemiological data on the23cross-section of the Chinese elderly patients with depression in Taiwan, the prevalence of depression was3.86%incidence of depression in rural areas dangerous rate of5.07%, higher than the city’s2.61%, much lower than the prevalence of Western countries.WHO(1993)Global Burden of Disease (GBD) studies have shown that the global burden of neuropsychiatric disease, depression, suicide, respectively,17.3%,15.9%, topped the list; depression accounted for disability-adjusted life years(DALY)4.2%; reduce depression and suicide accounted for5.9%. Prompt depression, suicide/self-injury in mental disorders lead to the loss of the burden of disease the biggest problem, attention should be paid. The study also predicted that by2020depression will become the following coronary heart disease after the second largest disease burden of the source. Forecast from1990to2020, China’s burden of neuropsychiatric disease increased from14.2%to15.5%, coupled with suicide and self-injury, and from18.1%to20.2%, accounting for1/5of the total burden of disease. Mental disorders and suicide share of the burden of disease will be ranked1,2(20.2%), depression, suicide and self-injury, and Alzheimer’s disease burden increased significantly, while depression is the main burden of mental illness problems (44%in1990to predict2020will be47%).Depressive disorder with high incidence, high recurrence, high disability characteristics, the consequences of a heavy economic burden, causing huge economic losses to society. United States (1994) in total health costs4%for the treatment of major depressive disorder, up to$43billion; of which only$9,000,000,000(28%) is the direct medical costs, and the remaining$34billion of patients with disease or disability caused by the loss. Diagnosis and treatment of the situation is not optimistic, lower overall recognition rate of depressive disorder, especially in the General Hospital. WHO multi-center collaborative research shows that15different countries or regions physician average recognition rate of depression was55.6%, Shanghai, China, the identification rate of21percent, far below the level of foreign Therefore, to enhance the prevention and treatment of depression, to find a positive and effective treatment, has a very important social and economic significance.The treatment of depression medication, psychotherapy, and ECT treatment of a variety of ways, the most common treatment remain antidepressant drug treatment. The relevant data show that10%-30%of patients for poor treatment response to antidepressants. In addition, for the therapy of antidepressant agents showed a lot of negative effects, such as decreased libido, nausea, vomiting, tremor, urinary block, physiological disorders, obesity, etc. Of SSRI and SNRI antidepressants side effects than traditional antidepressants weaken, but the mechanism of action and tricyclic drug is essentially the same, only for a single pathogenesis, only relieve some symptoms, not enough to take into account a variety of risk factors, depression can not solve a variety of problem incidence etiology and pathogenesis. And the efficacy and scope of application is not superior to conventional drugs, only50%of patients are completely relieved of symptoms. Its efficacy, onset latency, the pharmacological effects play a role can not be quickly resolved the patient complained of symptoms in2-4weeks.Venlafaxine is a5-serotonin and norepinephrine reuptake inhibitors, the mechanism of action of its dual activity in the treatment of depression than selective5 -HT reuptake inhibitors have an advantage, in the conversion strategycompared with SSRI has potential advantages. Safety and tolerability of the test statistics into the venlafaxine and SSRI side effects are nausea, vomiting, dry mouth and other digestive symptoms; dizziness, headaches and other neurological symptoms, no significant difference between the two. Prompt venlafaxine is a good safety and tolerability of antidepressants.Depression is a traditional Chinese medicine "depressive" category by qi stagnation, dysfunctional organs to the depressed, restless mood, chest stuffiness, flank pain, or irritability Yuku, or foreign body sensation in the pharynxdisease as the main clinical features. Understanding of the motherland medicine depressive for a long time, traditional Chinese medicine practitioners believe that the cause of depression has both internal and external, external because the emotional hurt, because dirty air, Yi Yu. Its pathogenesis is for qi stagnation, dysfunctional organs. The beginning of the depressive disease mainly to stagnation of qi, qi long time can cause blood stasis of the fire, phlegm knot, food stagnation, wet stop, and more true the card falling is easy to turn by the real imaginary, with its affect the organs and loss of blood, yin and yang are different, while the formation of a virtual lesion of heart, liver, spleen, kidney malfunction. The qi Gloomy builds easy is the basic principle of the treatment.The Modified Chaihuguizhi the soup national old TCM Professor Chen Baotian refer to the ancient and modern literature, on the basis of many years of clinical experience treating depression, after years of painstaking research, the important pathogenesis of depression, liver depression and exhausting, the by side Chaihuguizhi soupprepared on the basis of the Liver qi, stagnation and soothe the nerves of the level of yin and yang, five gods of the tune, and business health is characterized by the experience side. Chaihuguizhi soup Shugan Qi, phlegm achievements, raw Longmu and spiritual magnet town liver, Liver and Caulis, Fu Shen stagnation and soothe the nerves of various drugs to reach the liver and gas town liver Pinggan spleen and nourishing the heart, stagnation and sedative effect.In recent years, we have in clinical practice, using the Modified Chaihuguizhi soup merger venlafaxine treatment of depression carried out to obtain a certain effect. Clinical observation, combined with our previous treatment of moderate to severe depression in a retrospective analysis of flavored Chaihuguizhi soup combined with venlafaxine in the treatment efficacy. This topic will be more concerned about the mitigation of adverse reactions in patients with medication and to improve the situation, the efficacy and safety of traditional Chinese medicine to reduce the side effects of antidepressants to alleviate the core symptoms of depression and peripheral symptoms.Objective:Integrative efficacy and safety of the treatment of depression through a retrospective analysis of105patients with depression, further evaluation, especially of Chinese medicine in the antidepressant efficacy and alleviate Western medicine side effects. Objects and methods:1.ObjectsNanfang Hospital of Traditional Chinese Medicine clinic, ward and Chinese and Western medicine combined with the out-patient clinic of the Hospital encephalopathy in January2010to December2011, the ward diagnosis of depression in105patients.2.Inclusion and exclusion criteriaDiagnostic criteria of depression:are in line with the Chinese mental illness classification and diagnostic criteria3(CCMD-3) diagnostic criteria of depression. Inclusion criteria:(1) meet the diagnostic criteria of the CCMD-3depression cases;(2) Hamilton Depression Rating Scale (of HAMD-17) score≥17points;(3) gender and race is not restricted, inpatient and outpatient is not restricted;(4) age>18years;(5) Duration of≥30days or more;(6) Improve the routine examination, no significant serious organic disease;(7) the patients with completed12weeks of treatment.Exclusion criteria:(1) rule out other mental illnesses that do not meet the diagnostic criteria of the CCMD-3depression;(2) patients with the serious risk of suicide;(3) age<18years of age;(4) Improve the routine examination, associated with significant serious organic disease;(5) Pregnant women, lactating women;(6) The drug allergy;(7) Long-term use of psychotropic drugs and the dose of instability, monoamine oxidase inhibitors, lithium agents and valproic acid, carbamazepine and other antiepileptic agents;(8) Who do not meet the criteria for inclusion, not to take medication as prescribed, to determine the efficacy or infonnation is not congruent effects on efficacy and safety of judge.3.MethodsTest Method:A retrospective study.Patient selection criteria:diagnostic criteria, inclusion criteria and exclusion criteria. Diagnostic criteria with reference to the Chinese mental illness classification and diagnostic criteria3(CCMD-3) diagnostic criteria of depression, combined with traditional Chinese medicine dialectical standards.Therapy:the treatment group received venlafaxine sustained release tablets based on the joint the Modified Chaihuguizhi Tang (Bupleurum, Pinellia, Codonopsis, Licorice, Scutellaria, Cinnamon Twig, white peony root, ginger, jujube, Health keel, raw oystersspiritual magnet Caulis, Fu Shen, etc.); the control group was treated with venlafaxine sustained release tablets. Medication methods:two groups were treated with venlafaxine tablets, the treatment group combined with traditional Chinese flavored Chaihuguizhi soup. The treatment period of12weeks.Combination therapy provides that:during the treatment may not be combined for the use of any antipsychotic, antidepressant, mood stabilizer drugs. During the treatment of severe insomnia, can be an appropriate combination of zolpidem or alprazolam, zopiclone and short-acting benzodiazepines Zhuozhen Jing drugs, such as estazolam.Outcome measures:including demographic data, the impact of therapeutic factors, general physical examination and laboratory tests.Clinical criteria:Clinical criteria including depression, changes in scale scores before and after treatment.Observation of adverse events:the term covers of adverse events during clinical studies, the subjects and will affect the health of any clinical symptoms, the emergence or worsening of symptoms, syndrome, or certain diseases. Adverse events: new disease; treatment status of symptoms or signs of deterioration, or accompanied by the deterioration of the disease; the role of drug control; to participate in the trial; combination of one or more factors. Therefore, the term "adverse events" does not mean that a causal relationship to study drug.4.Statistical analysisAll data SPSS13.0statistical package for statistical analysis. The measurement data for the normality tests, such as the samples comply with the normal distribution with mean±standard deviation (±SD) said. Medication before and after each time point scale score change data using a repeated measures analysis of variance. After treatment, the HAMD reduction the sub efficacy analysis using generalized estimating equations (generalized estimating equations, GEE).Count data with the number of cases (%) said that the groups were analyzed using the X2test; such as data the theoretical value of<1, using Fisher’s exact test. Grade information Wilcoxon test was used. p<0.05was considered statistically significant.Results:1.HAMD scale score change:the difference between the two groups at different time points before and after administration were statistically significant (F=1204.507, P=0.000), treatment group, F=295.401, P=0.000, control group, F=167.256, P=0.000. HAMD scale score difference between the two groups was statistically significant (F=7.776, P=0.006) from each time point, with the exception of baseline HAMD scale score was no significant difference (t=-0.618, P=0.538), the medication for one week, two groups HAMD scale score differences were statistically significant (t=2weeks,4weeks,6weeks,8weeks-and12weeks-after-for2.654,3.397,3.203,2.840,3.322,3.821respectively, P=0.009,0.001,0.002,0.005,0.001,0.000), indicating that the medication from the patients at each time point, patients with depression HAMD scale scores decreased treatment group than the control group after one week. Between the two groups and taking time interaction effect (F=7.667, P=0.000), with the front at different time points between the two groups, multiple comparisons analysis coincide, indicating that changes in the two groups of patients with depression HAMD scale scores with to the medicine time to extend a downward trend.2.SDS scale score change:the difference between the two groups at different time points before and after administration were statistically significant (F=2012.564, P=0.000), treatment group, F=610.854, P=0.000, control group, F=68.278, P=0.000. SDS scale score differences between the two groups was statistically significant (F=116.876, P=0.000) from each time point of view, in addition to the baseline of SDS scale score difference was not statistically significant (t=-1.529, P=0.129), the medication for1week,2weeks,4weeks,6weeks,8weeks and12weeks after the two groups of SDS scale score differences were statistically significant (t=for3.037,7.126,11.466,16.711,21.326,23.747P value for0.003,0.000,0.000,0.000,0.000,0.000), show that the medication from patients at each time point, patients with depression SDS scale scores decreased treatment group than the control group after one week. Between the two groups and taking time interaction effect (F=258.781, P=0.000), with the front at different time points between the two groups, multiple comparisons analysis consistent, indicating that the two groups of patients with depression SDS scale score changes with to the medicine time to extend a downward trend.3.SAS scale score change:the difference between the two groups at different time points before and after administration were statistically significant (F=1123.184, P=0.000), treatment group, F=402.742, P=0.000, control group, F=60.464, P=0.000. SAS scale score difference between the two groups was statistically significant (F=92.576, P=0.000) from each time point of view, in addition to the baseline of SAS scale score difference was not statistically significant (t=-1.712, P=0.090), the medication for1week,2weeks,4weeks,6weeks,8weeks and12weeks after the two groups of SAS scale score differences were statistically significant (t=respectively2.209,6.873,12.002,17.548,17.172,18.394respectively,P=0.029,0.000,0.000,0.000,0.000,0.000), indicating that the medication from the patients at each time point, the depression scale scores of patients with SAS to reduce the magnitude of the treatment group than the control group after one week. Between the two groups and taking time interaction effect (F=150.707, P=0.000), with the front at different time points between the two groups, multiple comparisons analysis results coincide, indicating that changes in the two groups of depression scale scores of patients with SAS with to the medicine time to extend a downward trend. 4.HAMD sleep disturbance analysis:before and after administration there were significant differences between the two different time points (F=531.498, P=0.000) between the two groups and taking time interaction effect (F=7.657, P=0.000). Treatment group, F=137.232, P=0.000, control group, F=72.397, p=.000. Sleep disturbance score difference between the two groups was statistically significant (F=27.041, P=0.000) from each time point, with the exception of baseline sleep disturbance score was no significant difference (t=0.518, P=0.605). In addition, medication1week,2weeks,4weeks,6weeks,8weeks and12weeks after the two sets of sleep disturbance score differences were statistically significant (t=3.946,5.417,4.636,5.787,5.739,5.3575,Pvalueswere0.000,0.000,0.000,0.000,0.000,0.000), indicating that the two groups before treatment in patients with sleep disturbance score at the same level are comparable. At each time point from one week after the patients with medication, depression in patients with HAMD sleep disturbance score decreased treatment group than the control group.5.HAMD depressive and anxiety reaction analysis:before and after administration there were significant differences between the two different time points (F=546.509, P=0.000) between the two groups and taking time interaction effect (F=2.911,P<0.008). Treatment group, F=133.542, P=0.000, control group, F=79.791, p=.000. Depressive and anxiety reaction differences in scores between the two groups was statistically significant (F=2.032, P=0.157) from each time point, the baseline period and medication for one week, two weeks, four weeks, six weeks of depressive and anxiety reaction score was no significant difference(t=-0.658,1.368,1.904,1.573,1.444,Pvalueswere0.512,0.174,0.060,0.119,0.152), the two groups after8weeks and12weeks of depressive and anxiety reaction score difference was statistically significant (t=2.578,2.125,P values were0.011,0.037), indicating that the two groups of patients with depressive and anxiety reaction score at the same level before treatment, comparable, and since the patients taking a week,2weeks,4weeks,6weeks, two groups of depression in patients with HAMD depressive and anxiety reaction score lower of considerable magnitude. However, since patients with medication for eight weeks and12weeks of HAMD response of depressive and anxiety reaction decreased after the treatment group than the control group.6.HAMD apathy analysis:There were significant differences between the two groups at different time points before and after administration (F=125.812, P=0.000) between the two groups and taking the time does not exist an interaction effect (F=0.660, P=0.682). Treatment group, F=27.778, P=0.000, control group, F=19.172, p=.000. Between the two groups apathy score was no significant difference (F=0.003. P=0.954) from each time point, the baseline period and medication for1week,2weeks,4weeks,6weeks,8weeks,12weeks after two sets of apathy score differences were not statistically significant (t values were-0.801,0.036,0.343,0.521,-0.037,-0.174,-0.243, P value for0.425,0.971,0.732,0.604,0.9700.862,0.808), indicating that the two groups of patients with emotional indifference in the pre-treatment score at the same level are comparable, and medication from patients at different time points after one week, two groups of patients with depression HAMD apathy reduction of the score of considerable magnitude.7.HAMD somatic symptoms analysis:before and after administration there were significant differences between the two different time points (F=421.576, P=0.000) between the two groups and taking the time does not exist an interaction effect (F=1.675, P=0.125). Treatment group, F=114.595, P=0.000, control group, F=96.139, p=0.000. Somatic symptoms score differences between the two groups was statistically significant (F=0.886, P=.349) from each time point, the baseline period and medication for1week,2weeks,4weeks,6weeks,8weeks,12weeks the two groups after the somatic symptoms score differences were not statistically significant (t value were-0.418,1.447,1.186,1.583.0.904,0.472,0.399, P values were0.677,0.151,0.238,0.116,0.368,0.638,0.691) that before treatment in patients with somatic symptoms score at the same level are comparable, and medication from patients at different time points after one week, a considerable decrease of somatic symptoms in patients with HAMD scores of two groups of depression.8.HAMD points reduction efficacy analysis:Treatment group and control group (Z=3.82, P<0.001), treatment group than the control group; significant difference (Z=13.64, P<0.001) between the different time points, with time, the efficacy ofthe better; no interaction effect between group and time point (Z=-0.43, P=0.668).one week, two weeks after treatment,4weeks,6weeks,8weeks,12weeks each time point, treatment group and the level of efficacy in the control group Rank:55.63,49.50;61.85,41.20;60.50,43.00;63.21,39.39;58.83,45.22;60.43,43.09. The two groups after treatment at each time point differences were statistically significant (Z=-2.360, P=0.018; Z=-3.985, P<0.000; Z=-3.714, P<0.000; Z=-4.403, P <0.000; Z=-2.723, P=0.006; Z=-3.809, P<0.000).9.The onset time of analysis:one week of treatment, the treatment group and control group differences in the onset time was statistically significant (X2=16.293, P <0.000), treatment group,30%of patients the onset, while the control group did notapparent onset. In the first two weeks of treatment, treatment and control groups, more significant difference (X2=19.604, P<0.000), treatment group88.3%of patients on the onset time of onset, and control group, only48.9%in patients with onset.10.Treatment of the12th week cure rate:the treatment and control groups in clinical cure rates on the difference was statistically significant (X2=14.463, P0.000).12th week of treatment, the treatment group clinical cure rate was88.3%, while the control group, the clinical cure rate was only55.6%. 11.Analysis of adverse reactions:a variety of adverse effects of the treatment group were lower than the control group (X2=10.423, P<0.001), constipation (X2=6.099, P=0.014<0.05) and sexual dysfunction in both groups in the dry mouth (X2=4.257, P=0.039<0.05) differences compared to the incidence of statistically significant treatment group were significantly lower incidence of dry mouth, constipation and sexual dysfunction.Conclusions:1.Venlafaxine the Modified Chaihuguizhi soup merge text on the improvement of depression and with anxiety disorders is superior to single venlafaxine, but with the extension of the duration of treatment, the improvement of depression and anxiety disorders may be more stable.2.Modified Chaihuguizhi soup combined venlafaxine on sleep disorders to improve better than the venlafaxine group. Improvement in response to depression and anxiety, until after8weeks of treatment, venlafaxine group is superior to single, may be prompted with the treatment time, improve the efficacy of depression and anxiety reaction became clear. Of apathy and the improvement of physical symptoms, the efficacy of performance is not obvious.3.Modified Chaihuguizhi soup with venlafaxine clinical cure rate was88.3%, while only55.6%clinical cure rate in the venlafaxine group alone. Prompted the Modified Chaihuguizhi soup joint venlafaxine clinical cure rates may be higher than venlafaxine alone.4.Modified Chaihuguizhi soup combined venlafaxine30%in patients with onset during the first week, after two weeks of treatment, the onset of88.3percent. At the same time, a single venlafaxine only in the second week,48.9%in patients with onset. Tip the time of onset was significantly faster than venlafaxine alone.5.Modified Chaihuguizhi soup with venlafaxine may alleviate the side effects of venlafaxine in varying degrees, especially in reducing performance on adverse reactions such as dry mouth, constipation and sexual dysfunction may be more significant.

        加味柴胡桂枝湯合并文拉法辛治療中重度抑郁癥的回顧性研究

摘要3-12ABSTRACT12-25第一章 前言28-37    參考文獻(xiàn)34-37第二章 臨床研究37-66    第一節(jié) 研究對(duì)象37-39    第二節(jié) 研究方法39-43    第三節(jié) 研究結(jié)果43-66第三章 分析與討論66-83    一、抑郁癥的發(fā)病機(jī)制66-69    二、祖國(guó)醫(yī)學(xué)對(duì)抑郁癥的認(rèn)識(shí)69-72    三、肝郁傷神是本病的重要病機(jī)72    四、柴胡桂枝湯抗抑郁作用研究72    五、組方配伍及方義72-75    六、臨床療效分析75-79    參考文獻(xiàn)79-83第四章 全文總結(jié)83-85    一、主要研究結(jié)論83    二、展望與不足83-85綜述85-97    參考文獻(xiàn)93-97附錄97-104在讀期間發(fā)表論文情況104-105致謝105-107附件107

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