文拉法辛的不良反应认识进展（下）

于相芬，孙宇新，孙振晓*

（1 山东省临沂市精神卫生中心精神科，山东临沂276005；2山东大学医学院2013级临床医学系，济南 250012）

随着文拉法辛在临床上的广泛应用，对其不良反应的认识也不断深入，现对文拉法辛所致泌尿生殖系统、内分泌代谢系统、血液系统、神经系统不良反应、5-羟色胺（5-HT）综合征、横纹肌溶解症、精神方面不良反应和撤药综合征等概述如下。

1 泌尿生殖系统

1.1 尿失禁

Selvaraj 等报道1例66岁男性抑郁障碍患者应用文拉法辛75mg/d 1周内出现尿失禁，无论白天还是夜间均有不自主的尿失禁症状，停用文拉法辛后恢复[1]。Polimeni 等报道1例56岁女性反应性抑郁患者应用文拉法辛75mg/d治疗30天后出现尿失禁，停药48小时症状缓解，其后应用舍曲林治疗未再出现[2]。孙振晓等报道1例38岁女性抑郁障碍患者，应用文拉法辛治疗，首剂25mg，每日2次，4天后增至50mg,每日2次，增量后次日出现尿频尿急。继之出现尿失禁，停用文拉法辛4天后尿失禁消失，改用艾司西酞普兰治疗后未再出现尿失禁[3]。

1.2 尿频尿急

汪春运报道1例15岁男性抑郁障碍患者，应用文拉法辛25mg，每日3次治疗，4天后出现尿频尿急，减至25mg，每日2次，4天后尿路症状消失，再次增至25mg，每日3次，3天后又出现尿频尿急，再度减至25mg，每日2次，2天后尿路症状消失[4]。

1.3 尿潴留

Benazzi报道文拉法辛与氟哌啶醇联用致尿潴留1例[5]。

1.4 性功能障碍

已有文拉法辛致男性自发性性高潮[6]、性欲亢进[7]、阴茎异常勃起[8,9]及射精疼痛[10]的报道。

2 内分泌代谢系统

2.1 乳溢

Berilgen报道1例偏头痛患者应用文拉法辛治疗后出现晚发性乳溢及月经过多[11]。Sternbach 报道文拉法辛致乳溢1例[12]。

2.2 男性乳房发育

Karakurt等报道1例19岁男性广泛性焦虑障碍患者应用文拉法辛150mg/d治疗3个月后出现男性乳房发育，无乳溢，实验室检查显示血清催乳素、雌二醇和黄体生成素水平升高。停用文拉法辛后，肿块缩小，激素水平恢复正常[13]。

2.3 抗利尿激素分泌不当综合征

Meyer 等报道1例74岁女性慢性阻塞性肺病患者因呼吸困难入院，临床及实验室检查提示肺部感染而应用抗生素治疗。该患者因中重度抑郁发作而使用文拉法辛治疗3周，后出现低钠血症，血钠降至108 mmol/L，CT及实验室检查排除脑部及肺部、内分泌病变所致低钠血症，考虑为文拉法辛所致抗利尿激素分泌不当综合征。在未停用文拉法辛，也未严格限制进水量的情况下，患者又出现全身性癫痫发作。后应用托伐普坦治疗，48小时内血钠升至131mmol/L，也未再出现癫痫发作[14]。

2.4 低钠血症

Roxanas等报道58例65岁以上患者服用文拉法辛后，10例（17.2%）出现低钠血症，均发生于开始应用文拉法辛后数天。这可能与非抑制性抗利尿激素分泌有关。因其血浆渗透压低，通过限制液体进入，2周内恢复[15]。Grover 等报道文拉法辛引起低钠血症表现为紧张症1例[16]。

3 血液系统

3.1 出血

梁英等报道1例64岁男性抑郁障碍患者应用文拉法辛缓释胶囊渐增至150mg/d治疗，至第5周又增至225mg/d，增加剂量后第2天夜间及第3天清晨分别2次呕血，每次量约20ml,呈深红色，血常规、生化、电解质和凝血功能检查等未见异常，肿瘤标志物阴性，胸片检查亦未发现异常，将文拉法辛缓释胶囊减至150mg/d，未再出现呕血[17]。Ghio 等报道1例84岁女性应用文拉法辛导致上消化道出血[18]。也有文拉法辛致瘀斑[19,20]、牙龈出血[21]和阴道出血[22]等的报道。

3.2 粒细胞缺乏症

Lucht 等报道米安色林与文拉法辛联用致粒细胞缺乏症1例[23]。

4 神经系统

4.1 肌阵挛

Dutra 等报道1例混合型痴呆患者应用文拉法辛治疗发生肌阵挛[24]。

4.2 锥体外系反应

García-Parajuá 等报道文拉法辛致类帕金森综合征1例[25]。Grover等报道1例33岁女性Crohn病伴发复发性抑郁障碍患者既往应用文拉法辛75mg/d治疗，患者抑郁症状未完全缓解，将文拉法辛增至225mg/d治疗，在增加剂量后48小时内，患者出现静坐不能，停用后缓解[26]。Lee 等报道文拉法辛致迟发性眼睑痉挛 1 例[27]。

5 5-HT综合征

5-HT能药物因过度激动脑干和脊索的5-HT1A、5-HT2和5-HT3受体，引起5-HT综合征，表现为精神状态和行为的改变，运动系统功能改变，植物神经功能紊乱等症状[28]。Pan 等报道1例29岁女性抑郁障碍患者在应用文拉法辛37.5mg/d治疗期间发生5-HT综合征，表现不安、震颤、多汗、呕吐、共济失调、心动过速及肌阵挛，停用文拉法辛并应用普鲁氯嗪及劳拉西泮治疗2小时后恢复。2周后患者应用氟西汀20mg/d治疗未见不良反应[29]。5-HT综合征多为合并用药引起，Rajapakse 等报道1例43岁男性特发性帕金森病患者，在应用多巴胺能药物治疗期间，因抑郁合用文拉法辛治疗2周后，出现意识障碍、激越、多汗和运动过度入院，并出现严重横纹肌溶解及急性肾功能衰竭，诊断为5-HT综合征[30]。已有文拉法辛合并米氮平[31-32]、文拉法辛合并曲马多[33]、文拉法辛合并锂盐[34-36]、文拉法辛合并钙神经蛋白抑制剂[37]、文拉法辛合并美沙酮、环丙沙星[38]、文拉法辛合并曲马多、米氮平[39]、文拉法辛合并锂盐、丙戊酸盐[40]、文拉法辛合并单一剂量复合阿莫西林-克拉维酸[41]、文拉法辛合并苯环丙胺[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综合征的报道。

6 横纹肌溶解症

Huang等报道1例21岁女性双相抑郁患者应用低剂量文拉法辛后出现严重横纹肌溶解，几天内血清肌酸激酶水平增至18711U/L[47]。

7 精神方面

7.1 意识障碍

至今已有2例文拉法辛致谵妄的报道[48-49]。

7.2 感觉异常

Angelo等报道文拉法辛致感觉异常1例。该例系年轻男性抑郁障碍患者应用文拉法辛缓释剂37.5mg/d治疗，渐增至150mg/d，患者出现上肢刺痛、麻木和瘙痒，将剂量减至75mg/d，上肢刺痛、麻木和瘙痒症状消失。由于患者仍存在抑郁症状，又将剂量再增至150mg/d,患者上肢症状再现，减至75mg/d后,症状又消失[50]。

7.3 视幻觉

Tripp等报道1例44岁男性酒精依赖患者，因伴发抑郁应用文拉法辛75mg/d治疗，1周后患者出现视幻觉，幻觉持续1周后消失，期间文拉法辛剂量保持不变[51]。Jacob 等报道1例17岁男孩应用文拉法辛引起复杂性视幻觉[52]。

Gareri 等报道文拉法辛与普罗帕酮相互作用出现幻觉及精神运动性激越1例。患者为85岁女性，曾应用舍曲林治疗6个月，曾因高血压、室上性心动过速、慢性支气管炎及关节炎，服用雷米普利、噻氯匹定托拉塞米、茶碱、对乙酰氨基酚和三唑仑等药物治疗。患者也曾应用普罗帕酮治疗3年，用法为150mg,每12小时一次。患者血生化检查正常，颅脑CT检查显示皮质萎缩。因舍曲林疗效不佳，换用文拉法辛75mg/d，其他药物不变，4周后增至150mg/d，此剂量10天后患者出现视幻觉持续约2小时，并在晚上出现精神运动性激越，停用文拉法辛后，幻觉及精神运动性激越在4天内缓解[53]。

7.4 妄想

Safeekh 等报道1例32岁男性社交恐惧症患者应用文拉法辛150mg/d治疗后出现被害妄想，停药后恢复，应用艾司西酞普兰治疗后未再出现[54]。Admou 等报道1例39岁女性抑郁障碍患者在应用文拉法辛225-300mg/d治疗期间出现钟情妄想，剂量减至75-150mg/d后消失[55]。文拉法辛引起精神病性症状的机制可能与高剂量文拉法辛具有多巴胺再摄取抑制作用有关。Adamou等报道高剂量文拉法辛致色情狂1例[56]。

8 撤药综合征

文拉法辛撤药综合征的常见临床表现为胃肠道症状，如恶心、呕吐和腹泻等；不平衡感，如头昏、头重脚轻和眩晕等；一般躯体症状，如嗜睡、流感样症状、头痛、震颤、出汗和厌食等；感觉症状如感觉倒错、麻木、电击样感觉、头部“急流”感觉（rushing noise）和视力模糊等；情感症状，如易激惹、焦虑/激越、情绪低落和哭泣等；睡眠障碍，如失眠、噩梦和多梦等[57]。也有文拉法辛撤药出现躁狂[58]、耳鸣[59]、发作性睡眠[60]、持续后像[61]、遗精[62]、谵妄[63]及自杀意念[64]等的报道。

9 其他

尚有文拉法辛致盗窃癖[65]、腮腺肿大[66]、大脑血管收缩综合征[67]、夜间磨牙[68-70]、耳鸣[71-72]、乳房疼痛[73]、脱发[74-75]、银屑病样掌跖角皮症及指甲下角化过度[76]、局灶性肌炎[77]和诱发乳糜泻有关的显微镜结肠炎[78]等方面的报道。

临床医生在使用文拉法辛时，应严格掌握药物治疗的适应证和禁忌证，避免滥用药物，并应严密观察药物不良反应，及时发现，及时处理，确保用药安全。

[1]Selvaraj V,Gunasekar P,Kumar S,et al.Urinary Incontinence due to Overactive Detrusor Muscle: A Rare Side Effect of Venlafaxine[J]. Case Rep Urol,2015,2015:690931.

[2]Polimeni G,Salvo F,Cutroneo P,et al. Venlafaxine-induced urinary incontinence resolved after switching to sertraline[J]. Clin Neuropharmac ol,2005,28(5):247-248.

[3]孙振晓，于相芬.文拉法辛引起尿失禁[J].临床精神医学杂志，2011,21（5）：301.

[4]汪春运.每日口服文拉法辛75mg出现尿路症状1例[J].中国新药与临床杂志，2005,24（4）：331.

[5]Benazzi F. Urinary retention with venlafaxine-haloperidol combination[J]. Pha rmacopsychiatry,1997,30(1):27.

[6]Ravsten DV,Smith NB,Thatcher GW. Spontaneous male orgasm in association with venlafaxine[J]. Am Fam Physician,1997,55(5):1561, 1564, 1574.

[7]Warren MB. Venlafaxine-Associated Euprolactinemic Galactorrhea and Hypersexuality: A Case Report and Review of the Literature[J]. J Clin Psych opharmacol,2016,36(4):399-400.

[8]Samuel RZ. Priapism associated with venlafaxine use[J]. J Am Acad Child Adolesc Psychiatry,2000,39(1):16-17.

[9]Bolukbasi O,Akyol A. Spontaneous erections and libido increase associated with venlafaxine[J]. Eur J Neurol,1999,6(4):527-528.

[10]Michael A. Venlafaxine-induced painful ejaculation[J]. Br J Psychiatry,2000,177:282.

[11]Berilgen MS. Late-onset galactorrhea and menometrorrhagia with venlafaxine use in a migraine patient[J]. J Clin Psychopharmacol, 2010, 30(6):753-754.

[12]Sternbach H. Venlafaxine-induced galactorrhea[J]. J Clin Psychopharmac ol,2003,23(1):109-110.

[13]Karakurt F,Kargili A,Uz B,et al.Venlafaxine-induced gynecomastia in a young patient: a case report[J]. Clin Neuropharmacol, 2009, 32(1):51-52.

[14]Meyer I,Frank D,Janssens U. A case of venlafaxine-induced syndrome of inappropriate ADH secretion (SIADH) - treatment with tolvaptan[J]. Dtsch Med Wochenschr,2012,137(21):1096-1099.

[15]Roxanas M,Hibbert E,Field M.Venlafaxine hyponatraemia: incidence,mechanism and management[J]. Aust N Z J Psychiatry,2007,41(5):411-418.

[16]Grover S,Somaiya M,Ghormode D.Venlafaxine-associated hyponatremia presenting with catatonia[J]. J Neuropsychiatry Clin Neurosci,2013,25(2):E11-2.

[17]梁英，孙新宇，张兰兰.文拉法辛缓释胶囊致上消化道出血一例[J].国际精神病学杂志，2014,41（3）：191.

[18]Ghio L,Puppo S,Presta A.Venlafaxine and risk of upper gastrointestinal bleeding in elderly depression[J]. Curr Drug Saf,2012,7(5):389-390.

[19]Sarma A,Horne MK .Venlafaxine-induced ecchymoses and impaired platelet aggregation[J]. Eur J Haematol,2006,77(6):533-537.

[20]Carpenter JE,Fombi J,Udoka O,et al. Venlafaxine-Induced Bruising: A Case Report[J]. Prim Care Companion CNS Disord,2016,18(3). doi: 10.4088/PCC.15l01886.

[21]Yavasoglu I,Kadikoylu G,Bolaman Z. Gingival bleeding due to venlafaxine[J].Ann Pharmacother,2008,42(1):144-145.

[22]Linnebur SA,Saseen JJ,Pace WD. Venlafaxine-associated vaginal bleeding[J].Pharmacotherapy, 2002, 22(5): 652-655.

[23]Lucht MJ,Kleinschmidt R,Maier W,et al. Agranulocytosis during treatment with mianserin and venlafaxine[J]. J Clin Psychopharmacol, 2000,20(4):490-491.

[24]Dutra LA,Pedroso JL,Felix EP,et al. Venlafaxine induced-myoclonus in a patient with mixed dementia[J]. Arq Neuropsiquiatr,2008,66(4):894-895.

[25]García-Parajuá P,Alvarez Iniesta I,Magariños M. Reversible and dose-related parkinsonism induced by venlafaxine[J]. Med Clin(Barc),2003,120(19):759.

[26]Grover S,Valaparla VL. Venlafaxine induced akathisia: a case report[J].Indian J Pharmacol,2014,46(6):660-661.

[27]Lee Y,Yeh WC,Chong MY,et al. Venlafaxine and tardive blepharospasm:a case report[J]. Prog Neuropsychopharmacol Biol Psychiat ry,2007,31(5):1139-1140.

[28]喻东山,葛茂宏.精神科合理用药手册[M].2版.南京：江苏科学技术出版社，2011:195-201.

[29]Pan JJ,Shen WW. Serotonin syndrome induced by low-dosevenlafaxine[J].Ann Pharmacother,2003,37(2):209-211.

[30]Rajapakse S,Abeynaike L,Wickramarathne T.Venlafaxine-associated serotonin syndrome causing severe rhabdomyolysis and acute renal failure in a patient with idiopathic Parkinson disease[J]. J Clin Psychopharmacol,2010,30(5):620-622.

[31]Decoutere L,De Winter S,Vander Weyden L,et al.A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and rechallenge[J]. Int J Clin Pharm,2012, 34(5): 686-688.

[32]Dimellis D. Serotonin syndrome produced by a combination of venlafaxine and mirtazapine[J]. World J Biol Psychiatry,2002,3(3):167.

[33]Albiñana Pérez MS,Cea Pereira L, Bilbao Salcedo J,et al. Possible serotonin syndrome associated with administration of venlafaxine and tramadol[J].Farm Hosp,2012,36(6):548.

[34]Shahani L. Venlafaxine augmentation with lithium leading to serotonin syndrome[J]. J Neuropsychiatry Clin Neurosci,2012,24(3):E47.

[35]Adan-Manes J,Novalbos J,López-Rodríguez R,et al. Lithium and venlafaxine interaction: a case of serotonin syndrome[J]. J Clin Pharm Ther,2006,31(4):397-400.

[36]Mekler G,Woggon B. A case of serotonin syndrome caused by venlafaxine and lithium[J]. Pharmacopsychiatry,1997,30(6):272-273.

[37]Newey CR,Khawam E,Coffman K. Two cases of serotonin syndrome with venlafaxine and calcineurin inhibitors[J]. Psychosomatics, 2011,52(3): 286-290.

[38]Lee J,Franz L,Goforth HW. Serotonin syndrome in a chronic-pain patient receiving concurrent methadone, ciprofloxacin, andvenlafaxine[J]. Psychoso matics,2009,50(6):638-639.

[39]Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine[J]. Ann Pharmacoth er,2004,38(3):411-413.

[40]Liberek C,Aubry JM,Baud P. Manic switch and serotonin syndrome with venlafaxine-lithium-valproate association[J].Therapie,2006,61(6):531-533.

[41]Connor H. Serotonin syndrome after single doses of co-amoxiclav during treatment with venlafaxine[J]. J R Soc Med,2003,96(5):233-234.

[42]Hodgman MJ,Martin TG,Krenzelok EP. Serotonin syndrome due to venlafaxine and maintenance tranylcypromine therapy[J]. Hum Exp Toxicol,1997,16(1):14-17.

[43]Brubacher JR,Hoffman RS,Lurin MJ. Serotonin syndrome from venlafaxinetranylcypromine interaction[J]. Vet Hum Toxicol,1996,38(5):358-361.

[44]Dougherty JA,Young H,Shafi T. Serotonin syndrome induced by amitriptyline, meperidine, and venlafaxine[J]. Ann Pharmacoth er,2002,36(10):1647-1648.

[45]Weiner LA,Smythe M,Cisek J. Serotonin syndrome secondary to phenelzinevenlafaxine interaction[J]. Pharmacotherapy,1998,18(2):399-403.

[46]Pinel-Ríos FJ,Peñuelas-Calvo I,Cerezo-Ramírez N,et al. Serotonin syndrome induced by a combination of venlafaxine and clomipramine. A case report[J]. Actas Esp Psiquiatr, 2016,44(5): 193-202.

[47]Huang SS,Yang HY,Lin YC,et al. Low-dose venlafaxine-induced severe rhabdomyolysis: a case report[J]. Gen Hosp Psychiatry, 2012,34(4):436.e5-7.

[48]del Río-Casanova L,Portela B,Díaz-Llenderrozas F. Venlafaxineinduced delirium mediated by high doses[J]. Rev Neurol,2015 ,60(10):475-477.

[49]Howe C,Ravasia S. Venlafaxine-induced delirium[J]. Can J Psychiatry,2003,48(2):129.

[50]Angelo LJ,Lee KC.Dose-related paresthesias with venlafaxine[J]. J Pharm Pract,2013, 26(5):514-517.

[51]Tripp AC,Golden SA. Transient Complex Visual Hallucinations With Venlafaxine Treatment: A Case Report[J]. Prim Care Companion J Clin Psychiatry, 2009; 11(2): 83.

[52]Jacob MK,Ash P. Venlafaxine-induced complex visual hallucinations in a 17-year-old boy[J]. J Clin Psychiatry,2009, 70(4):601-603.

[53]Gareri P,De Fazio P,Gallelli L,et al.Venlafaxine-propafenone interaction resulting in hallucinations and psychomotor agitation[J]. Ann Pharmacoth er,2008,42(3):434-438.

[54]Safeekh AT,Pinto D. Venlafaxine-induced psychotic symptoms[J]. Indian J Psychiatry,2009,51(4):308-309.

[55]Adamou M, Hale AS. Erotomania induced by venlafaxine: A case study[J].Acta Psychiatr Scand,2003,107:314–317.

[56]Adamou M,Hale AS. Erotomania induced by venlafaxine: a case study[J].Acta Psychiatr Scand,2003,107(4):314-317.

[57]Haddad PM,Anderson IM.Recognising and managing antidepressant discontinuation symptoms[J].Advance in Psychiatric Treatment,2007,13:447-457.

[58]Fava GA,Mangelli L.Mania associated with venlafaxine discontinuation[J].Int J Neuropsychopharmacol,2003, 6(1): 89-90.

[59]Clewes J.A case report of onset of tinnitus following discontinuation of antidepressant and a review of the literature[J].Prim Care Companion CNS Disord,2012,14(1).pii:PCC. 11br01218.

[60]Nissen C,Feige B,Nofzinger E,et al.Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine[J].J Sleep Res,2005,14(2):207-208.

[61]Spindler PE.Palinopsia following discontinuation of venlafaxine[J]. Psychiatr Prax,2008,35(5):255-257.

[62]孙振晓.文拉法辛缓释片撤药致遗精一例报告[J].精神医学杂志，2015,28（1）：73.

[63]van Noorden MS,Vergouwen AC,Koerselman GF.Delirium during withdrawl of venlafaxine[J].Ned Tijdschr Geneeskd,2002, 146(26): 1236- 1237.

[64]Stone TE,Swanson C,Feldman MD.Venlafaxine discontinuation syndrome and suicidal ideation:a case series[J].J Clin Psychopharmacol,2007,27(1):94-95.

[65]Demartini B,D’Agostino A,Basi C,et al. A case of venlafaxine-induced kleptomania[J]. Eur J Clin Pharmacol,2016,72(4):509-510.

[66]Bonnet U,Khalil-Boutros Y.Acute bilateral parotitis occurring during venlafaxine titration in an adolescent female with major depression[J]. Phar macopsychiatry,2014,47(1):36-38.

[67]Davies G,Wilson H,Wilhelm T,et al. The reversible cerebral vasoconstriction syndrome in association with venlafaxine and methenamine[J]. BMJ Case Rep,2013 Jun 13;2013. pii: bcr2013009701.

[68]Alonso-Navarro H,Martín-Prieto M,Ruiz-Ezquerro JJ,et al.Bruxism possibly induced by venlafaxine[J]. Clin Neuropharmac ol,2009,32(2):111-112.

[69]Kuloglu M,Ekinci O,Caykoylu A. Venlafaxine-associated nocturnal bruxism in a depressive patient successfully treated with buspirone[J]. J Psychophar macol,2010,24(4):627-628.

[70]Sam Padamadan Jose. Venlafaxine-Induced Severe Sleep Bruxism in a Patient with Generalized Anxiety Disorder[J]. Indian J Psychol Med,2015,37(2): 249–250.

[71]Pondrom MF,Brahm NC. Venlafaxine-associated tinnitus[J]. Am J Health Syst Pharm,2009,66(18):1606, 1608.

[72]Ahmad S. Venlafaxine and severe tinnitus[J]. Am Fam Physician,1995,51(8):1830.

[73]Bhatia SC,Gupta S,Theesen KA. Breast pain associated with venlafaxine[J]. J Clin Psychiatry,1996,57(9):423.

[74]Pereira CE,Goldman-Levine JD. Extended-release venlafaxine-induced alopecia[J]. Ann Pharmacother,2007,41(6):1084.

[75]Pitchot W,Ansseau M. Venlafaxine-induced hair loss[J]. Am J Psychiatry,2001, 158(7): 1159-1160.

[76]Dalle S,Becuwe C,Balme B,et al. Venlafaxine-associated psoriasiform palmoplantar keratoderma and subungual hyperkeratosis[J]. Br J Dermatol,2006,154(5):999-1000.

[77]Jewell DP,Thompson IW,Sullivan BA,et al. Reversible focal myositis in a patient taking venlafaxine[J]. Rheumatology (Oxford),2004, 43(12):1590-1593.

[78]Béchade D,Carmoi T,Bonnefoy S,et al. Microscopic colitis associated with celiac disease probably triggered by the administration of venlafaxine[J].Rev Med Interne,2009,30(1):74-77.