于相芬，孫宇新，孫振曉*

（1 山東省臨沂市精神衛(wèi)生中心精神科，山東臨沂276005；2山東大學(xué)醫(yī)學(xué)院2013級臨床醫(yī)學(xué)系，濟(jì)南 250012）

隨著文拉法辛在臨床上的廣泛應(yīng)用，對其不良反應(yīng)的認(rèn)識也不斷深入，現(xiàn)對文拉法辛所致泌尿生殖系統(tǒng)、內(nèi)分泌代謝系統(tǒng)、血液系統(tǒng)、神經(jīng)系統(tǒng)不良反應(yīng)、5-羥色胺（5-HT）綜合征、橫紋肌溶解癥、精神方面不良反應(yīng)和撤藥綜合征等概述如下。

1 泌尿生殖系統(tǒng)

1.1 尿失禁

Selvaraj 等報道1例66歲男性抑郁障礙患者應(yīng)用文拉法辛75mg/d 1周內(nèi)出現(xiàn)尿失禁，無論白天還是夜間均有不自主的尿失禁癥狀，停用文拉法辛后恢復(fù)[1]。Polimeni 等報道1例56歲女性反應(yīng)性抑郁患者應(yīng)用文拉法辛75mg/d治療30天后出現(xiàn)尿失禁，停藥48小時癥狀緩解，其后應(yīng)用舍曲林治療未再出現(xiàn)[2]。孫振曉等報道1例38歲女性抑郁障礙患者，應(yīng)用文拉法辛治療，首劑25mg，每日2次，4天后增至50mg,每日2次，增量后次日出現(xiàn)尿頻尿急。繼之出現(xiàn)尿失禁，停用文拉法辛4天后尿失禁消失，改用艾司西酞普蘭治療后未再出現(xiàn)尿失禁[3]。

1.2 尿頻尿急

汪春運(yùn)報道1例15歲男性抑郁障礙患者，應(yīng)用文拉法辛25mg，每日3次治療，4天后出現(xiàn)尿頻尿急，減至25mg，每日2次，4天后尿路癥狀消失，再次增至25mg，每日3次，3天后又出現(xiàn)尿頻尿急，再度減至25mg，每日2次，2天后尿路癥狀消失[4]。

1.3 尿潴留

Benazzi報道文拉法辛與氟哌啶醇聯(lián)用致尿潴留1例[5]。

1.4 性功能障礙

已有文拉法辛致男性自發(fā)性性高潮[6]、性欲亢進(jìn)[7]、陰莖異常勃起[8,9]及射精疼痛[10]的報道。

2 內(nèi)分泌代謝系統(tǒng)

2.1 乳溢

Berilgen報道1例偏頭痛患者應(yīng)用文拉法辛治療后出現(xiàn)晚發(fā)性乳溢及月經(jīng)過多[11]。Sternbach 報道文拉法辛致乳溢1例[12]。

2.2 男性乳房發(fā)育

Karakurt等報道1例19歲男性廣泛性焦慮障礙患者應(yīng)用文拉法辛150mg/d治療3個月后出現(xiàn)男性乳房發(fā)育，無乳溢，實(shí)驗(yàn)室檢查顯示血清催乳素、雌二醇和黃體生成素水平升高。停用文拉法辛后，腫塊縮小，激素水平恢復(fù)正常[13]。

2.3 抗利尿激素分泌不當(dāng)綜合征

Meyer 等報道1例74歲女性慢性阻塞性肺病患者因呼吸困難入院，臨床及實(shí)驗(yàn)室檢查提示肺部感染而應(yīng)用抗生素治療。該患者因中重度抑郁發(fā)作而使用文拉法辛治療3周，后出現(xiàn)低鈉血癥，血鈉降至108 mmol/L，CT及實(shí)驗(yàn)室檢查排除腦部及肺部、內(nèi)分泌病變所致低鈉血癥，考慮為文拉法辛所致抗利尿激素分泌不當(dāng)綜合征。在未停用文拉法辛，也未嚴(yán)格限制進(jìn)水量的情況下，患者又出現(xiàn)全身性癲癇發(fā)作。后應(yīng)用托伐普坦治療，48小時內(nèi)血鈉升至131mmol/L，也未再出現(xiàn)癲癇發(fā)作[14]。

2.4 低鈉血癥

Roxanas等報道58例65歲以上患者服用文拉法辛后，10例（17.2%）出現(xiàn)低鈉血癥，均發(fā)生于開始應(yīng)用文拉法辛后數(shù)天。這可能與非抑制性抗利尿激素分泌有關(guān)。因其血漿滲透壓低，通過限制液體進(jìn)入，2周內(nèi)恢復(fù)[15]。Grover 等報道文拉法辛引起低鈉血癥表現(xiàn)為緊張癥1例[16]。

3 血液系統(tǒng)

3.1 出血

梁英等報道1例64歲男性抑郁障礙患者應(yīng)用文拉法辛緩釋膠囊漸增至150mg/d治療，至第5周又增至225mg/d，增加劑量后第2天夜間及第3天清晨分別2次嘔血，每次量約20ml,呈深紅色，血常規(guī)、生化、電解質(zhì)和凝血功能檢查等未見異常，腫瘤標(biāo)志物陰性，胸片檢查亦未發(fā)現(xiàn)異常，將文拉法辛緩釋膠囊減至150mg/d，未再出現(xiàn)嘔血[17]。Ghio 等報道1例84歲女性應(yīng)用文拉法辛導(dǎo)致上消化道出血[18]。也有文拉法辛致瘀斑[19,20]、牙齦出血[21]和陰道出血[22]等的報道。

3.2 粒細(xì)胞缺乏癥

Lucht 等報道米安色林與文拉法辛聯(lián)用致粒細(xì)胞缺乏癥1例[23]。

4 神經(jīng)系統(tǒng)

4.1 肌陣攣

Dutra 等報道1例混合型癡呆患者應(yīng)用文拉法辛治療發(fā)生肌陣攣[24]。

4.2 錐體外系反應(yīng)

García-Parajuá 等報道文拉法辛致類帕金森綜合征1例[25]。Grover等報道1例33歲女性Crohn病伴發(fā)復(fù)發(fā)性抑郁障礙患者既往應(yīng)用文拉法辛75mg/d治療，患者抑郁癥狀未完全緩解，將文拉法辛增至225mg/d治療，在增加劑量后48小時內(nèi)，患者出現(xiàn)靜坐不能，停用后緩解[26]。Lee 等報道文拉法辛致遲發(fā)性眼瞼痙攣 1 例[27]。

5 5-HT綜合征

5-HT能藥物因過度激動腦干和脊索的5-HT1A、5-HT2和5-HT3受體，引起5-HT綜合征，表現(xiàn)為精神狀態(tài)和行為的改變，運(yùn)動系統(tǒng)功能改變，植物神經(jīng)功能紊亂等癥狀[28]。Pan 等報道1例29歲女性抑郁障礙患者在應(yīng)用文拉法辛37.5mg/d治療期間發(fā)生5-HT綜合征，表現(xiàn)不安、震顫、多汗、嘔吐、共濟(jì)失調(diào)、心動過速及肌陣攣，停用文拉法辛并應(yīng)用普魯氯嗪及勞拉西泮治療2小時后恢復(fù)。2周后患者應(yīng)用氟西汀20mg/d治療未見不良反應(yīng)[29]。5-HT綜合征多為合并用藥引起，Rajapakse 等報道1例43歲男性特發(fā)性帕金森病患者，在應(yīng)用多巴胺能藥物治療期間，因抑郁合用文拉法辛治療2周后，出現(xiàn)意識障礙、激越、多汗和運(yùn)動過度入院，并出現(xiàn)嚴(yán)重橫紋肌溶解及急性腎功能衰竭，診斷為5-HT綜合征[30]。已有文拉法辛合并米氮平[31-32]、文拉法辛合并曲馬多[33]、文拉法辛合并鋰鹽[34-36]、文拉法辛合并鈣神經(jīng)蛋白抑制劑[37]、文拉法辛合并美沙酮、環(huán)丙沙星[38]、文拉法辛合并曲馬多、米氮平[39]、文拉法辛合并鋰鹽、丙戊酸鹽[40]、文拉法辛合并單一劑量復(fù)合阿莫西林-克拉維酸[41]、文拉法辛合并苯環(huán)丙胺[42,43]、文拉法辛合并阿米替林、哌替啶[44]、文拉法辛合并苯乙肼[45]、文拉法辛合并氯米帕明[46]等引起5-HT綜合征的報道。

6 橫紋肌溶解癥

Huang等報道1例21歲女性雙相抑郁患者應(yīng)用低劑量文拉法辛后出現(xiàn)嚴(yán)重橫紋肌溶解，幾天內(nèi)血清肌酸激酶水平增至18711U/L[47]。

7 精神方面

7.1 意識障礙

至今已有2例文拉法辛致譫妄的報道[48-49]。

7.2 感覺異常

Angelo等報道文拉法辛致感覺異常1例。該例系年輕男性抑郁障礙患者應(yīng)用文拉法辛緩釋劑37.5mg/d治療，漸增至150mg/d，患者出現(xiàn)上肢刺痛、麻木和瘙癢，將劑量減至75mg/d，上肢刺痛、麻木和瘙癢癥狀消失。由于患者仍存在抑郁癥狀，又將劑量再增至150mg/d,患者上肢癥狀再現(xiàn)，減至75mg/d后,癥狀又消失[50]。

7.3 視幻覺

Tripp等報道1例44歲男性酒精依賴患者，因伴發(fā)抑郁應(yīng)用文拉法辛75mg/d治療，1周后患者出現(xiàn)視幻覺，幻覺持續(xù)1周后消失，期間文拉法辛劑量保持不變[51]。Jacob 等報道1例17歲男孩應(yīng)用文拉法辛引起復(fù)雜性視幻覺[52]。

Gareri 等報道文拉法辛與普羅帕酮相互作用出現(xiàn)幻覺及精神運(yùn)動性激越1例?；颊邽?5歲女性，曾應(yīng)用舍曲林治療6個月，曾因高血壓、室上性心動過速、慢性支氣管炎及關(guān)節(jié)炎，服用雷米普利、噻氯匹定托拉塞米、茶堿、對乙酰氨基酚和三唑侖等藥物治療?；颊咭苍鴳?yīng)用普羅帕酮治療3年，用法為150mg,每12小時一次。患者血生化檢查正常，顱腦CT檢查顯示皮質(zhì)萎縮。因舍曲林療效不佳，換用文拉法辛75mg/d，其他藥物不變，4周后增至150mg/d，此劑量10天后患者出現(xiàn)視幻覺持續(xù)約2小時，并在晚上出現(xiàn)精神運(yùn)動性激越，停用文拉法辛后，幻覺及精神運(yùn)動性激越在4天內(nèi)緩解[53]。

7.4 妄想

Safeekh 等報道1例32歲男性社交恐懼癥患者應(yīng)用文拉法辛150mg/d治療后出現(xiàn)被害妄想，停藥后恢復(fù)，應(yīng)用艾司西酞普蘭治療后未再出現(xiàn)[54]。Admou 等報道1例39歲女性抑郁障礙患者在應(yīng)用文拉法辛225-300mg/d治療期間出現(xiàn)鐘情妄想，劑量減至75-150mg/d后消失[55]。文拉法辛引起精神病性癥狀的機(jī)制可能與高劑量文拉法辛具有多巴胺再攝取抑制作用有關(guān)。Adamou等報道高劑量文拉法辛致色情狂1例[56]。

8 撤藥綜合征

文拉法辛撤藥綜合征的常見臨床表現(xiàn)為胃腸道癥狀，如惡心、嘔吐和腹瀉等；不平衡感，如頭昏、頭重腳輕和眩暈等；一般軀體癥狀，如嗜睡、流感樣癥狀、頭痛、震顫、出汗和厭食等；感覺癥狀如感覺倒錯、麻木、電擊樣感覺、頭部“急流”感覺（rushing noise）和視力模糊等；情感癥狀，如易激惹、焦慮/激越、情緒低落和哭泣等；睡眠障礙，如失眠、噩夢和多夢等[57]。也有文拉法辛撤藥出現(xiàn)躁狂[58]、耳鳴[59]、發(fā)作性睡眠[60]、持續(xù)后像[61]、遺精[62]、譫妄[63]及自殺意念[64]等的報道。

9 其他

尚有文拉法辛致盜竊癖[65]、腮腺腫大[66]、大腦血管收縮綜合征[67]、夜間磨牙[68-70]、耳鳴[71-72]、乳房疼痛[73]、脫發(fā)[74-75]、銀屑病樣掌跖角皮癥及指甲下角化過度[76]、局灶性肌炎[77]和誘發(fā)乳糜瀉有關(guān)的顯微鏡結(jié)腸炎[78]等方面的報道。

臨床醫(yī)生在使用文拉法辛?xí)r，應(yīng)嚴(yán)格掌握藥物治療的適應(yīng)證和禁忌證，避免濫用藥物，并應(yīng)嚴(yán)密觀察藥物不良反應(yīng)，及時發(fā)現(xiàn)，及時處理，確保用藥安全。

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