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Recurrence of suicidal ideation due to treatment with antidepressants in anxiety disorder a case report 用抗抑郁药治疗焦虑症导致自杀意念再次出现 病例报告.doc

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Recurrence of suicidal ideation due to treatment with antidepressants in anxiety disorder a case report 用抗抑郁药治疗焦虑症导致自杀意念再次出现 病例报告.doc

Recurrenceofsuicidalideationduetotreatmentwithantidepressantsinanxietydisorderacasereport用抗抑郁药治疗焦虑症导致自杀意念再次出现病例报告DoronTodder1andBernhardTBaune2,31DepartmentofPsychiatry,BenGurionUniversity,BeerSheva,Israel2DepartmentofPsychiatry,UniversityofMuenster,Germany3DepartmentofPsychiatry,JamesCookUniversity,AustraliaauthoremailcorrespondingauthoremailJournalofMedicalCaseReports2007,1166doi10.1186/175219471166TheelectronicversionofthisarticleisthecompleteoneandcanbefoundonlineReceived3September2007Accepted3December2007Published3December2007©2007TodderandBaunelicenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicensewhichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.Abstract摘要ThisreportdescribesapatientsufferingfrompanicdisorderwhodevelopedrepeatedsuicidalideationspecificallyduetothetreatmentwithVenlafaxine.AfirstsuicideattemptyearsagooccurredwhilebeingtreatedwithVenlafaxine.SubsequenttreatmentwithSSRIsorotherantidepressantsinvolvednosuicidalideation.RecommencementofVenlafaxinefouryearslaterimmediatelyledtoasecondsuicideattempt.ThisunwantedeffectsubsidedimmediatelyafterswitchingtoanotherSNRIi.e.Duloxetine.Thecasereportunderlinestheimportanceofonsetofsuicideriskinpanicdisordersduetospecificantidepressants.本报告描述的是一名惊恐障碍患者反复出现由文拉法辛治疗特定导致的自杀意念。患者数年前用文拉法辛治疗时首次出现自杀企图。后来用SSRI(选择性5羟色胺再摄取抑制剂)或其他抗抑郁药未出现自杀意念。4年后重新开始用文拉法辛治疗,随即导致了第二次自杀企图。将药物更换为另一种SNRI(选择性去甲肾上腺素再摄取抑制剂)(度洛西汀)后,此副作用迅速消退。本病例报告强调了治疗惊恐障碍时,特效抗抑郁药导致出现自杀风险的重要性。Introduction引言SincetheintroductionofthefirstspecificserotoninreuptakeinhibitorsSSRIFluoxetine,aconcernemergedregardingtheriskofdevelopingsuicideideationasararesideeffect1.During2003,BritainsCommitteeonSafetyofMedicinesissuedawarningaboutthedangersofdevelopingsuicideassideeffect,firstforParoxetineandthenextendedthewarningtoallthenewantidepressants2.TheUSAFoodandDrugAdministrationfollowed,embracingthewarningforchildren,andthenextendedthewarningtoadults3.由于首个特效5羟色胺再摄取抑制剂SSRI氟西汀的出现,人们开始担心会出现自杀意念这一罕见副作用的风险1。2003年,英国药物安全委员会发布警告帕罗西汀有导致自杀这一副作用的危险,随后将警告扩展至所有新型抗抑郁药2。美国食品与药品管理局随即也开始对儿童发出警告,后来也将警告扩展至成人3。Mostofthecasereportsthatwerepublishedonthesubjectdealtwithdepressivepatients.Someofthesecasereportsdescribedtreatmentresistantpatientsorpatientswhoweretreatedwithhigherthancommonpracticedrugdoses.Allthesedrawbackslimitedtheabilitytoreachconclusiveanswersregardingthetrueconnectionbetweensuicideandantidepressanttreatment4.已发表的关于此问题的病例报告大多涉及抑郁患者。其中,部分病例报告描述的是对治疗耐受的患者或以高于常用药物剂量的剂量治疗的患者。所有这些缺点限制了就自杀于抗抑郁药治疗之间的真实联系得出最终结论4。Thefollowingdescriptionofapatientisuniquebecausehesufferedfromanxietydisorderandwasneitherdepressednorexperiencingsuicideideationpriortothebeginningoftheantidepressanttreatment.Thiscasehighlightstheidiosyncraticresponseofsuicidalideationemergingfromthetreatmentwithantidepressants.下文对患者的描述的独特之处在于,他患有焦虑症,开始抗抑郁治疗之前既没有抑郁,也没有出现过自杀意念。本病例突出了抗抑郁药治疗期间出现自杀意念的异质性反应。Casepresentation病例描述Wereportona19yearoldmalepatientwhosuffersfrompanicdisorderaccordingtotheDSMIVDiagnosticandStatisticalManualofMentalDisorders,versionIV5criteriasincetheageof15.Hewasalsodiagnosedwithcomorbidnarcissisticpersonalitydisorder,butwithoutanydrugoralcoholabuseinthepast.Nomedicalorotherhealthproblemswereknownorpresent.Onsetofpanicattackswasatage15whenhisparentsdivorced.InitialpharmacologicaltreatmentwithFluoxetine20mgtiteredupwithinafewweekswascombinedwithindividualandfamilypsychotherapyonanoutpatientlevel.DuetolackofresponsethepatientwasswitchtoFluvoxamine150mgafter2months.Despitethisintensifiedtreatmentregimen,panicattackscontinuedandhisoverallstatedeterioratedeventuallyleadingtohospitalizationtoayouthinpatientward.TreatmentwaschangedtoVenlafaxineinitiallywith75mg/dayinthemorning.Almostimmediatelythepatientexperiencedfrequentsuicidethoughtsalongwithfeelingsofdespairandhopelessness.Thethoughtsfrightenedhimtothepointofsufferingfrequentpanicattacks.Thisdeteriorationwasinterpretedasasignoftreatmentresistanceandtherefore,Venlafaxinewastiteredupto300mg/day.Subsequently,thepatientmadehisfirstsuicideattemptbydrinkingacidthatwasleftbyacarelesshospitalworker.Nopsychosocialfactorsorstressfullifeeventsweredetectedtohavecontributedtothesuicideattempt.我们在此报告的是一名患有惊恐障碍的19岁男性,他是在15岁时根据DSMIV(精神疾病诊断与统计手册,第4版)5标准被确诊的。他还被诊断出同时患有自恋型人格障碍,但既往没有用过任何药物,无酒精滥用史。未知或未见医学或其他健康问题。患者15岁时父母离异,当年首次出现了惊恐发作。最初在门诊用氟西汀20mg(数周内逐渐滴定增大剂量)联合个人和家庭心理治疗。由于患者对治疗反应不佳,2个月后将药物换为氟伏沙明150mg。虽然更换为此强化治疗方案,患者仍发生惊恐发作,整体状态逐渐恶化,最终入住青年病房住院治疗。治疗方案改为初始早上服用文拉法辛75mg/天。服药后患者随即频繁出现自杀念头,伴有绝望和无助感。自杀念头使他受到了惊吓,惊恐发作频繁发生。这种病情恶化被解释为治疗耐受的表现,因此,文拉法辛滴定增大剂量300mg/天。后来,患者喝了医院工人疏忽留下的酸,首次企图自杀。未发现导致此次自杀企图的心理社会因素或应激生活事件。Followingthisevent,Paroxetinewastrialedupto20mg/dleadingtoalmostfullremissionandonlyrarepanicattacksduringthefollowing4weeks.Atthatpointintime,whenthepatientwasdischargedhome,hisgeneralfunctioningwasnormal.Inthenext4yearsthepatientcontinuedonParoxetine20mg/dbecausewhenhetriedloweringthisdoseaccordingtohispsychiatrist,hefeltmoreanxious.Hewasregularlyfollowedupduringthistimeandexperiencedrareclassicpanicattacksmostlyduringstressfultimes.患者自杀未遂后,试用帕罗西汀20mg/天,随后4周患者几乎完全缓解,惊恐发作很少出现。经过一段时间后患者出院回家,当时他的一般功能是正常的。随后4年,患者依照精神科医师的医嘱试图减少帕罗西汀的剂量时就会感到焦虑加重,因此他继续用20mg/天。这段时间内他定期随访,在应激期内基本上很少发生典型的惊恐发作。After4yearsofcontinuousantidepressanttreatmentwithParoxetine,thepatientstartedtocomplainaboutdelayedejaculationwhichwasattributedtoParoxetine.Asaconsequenceotherantidepressantsweretrialed,noneofwhichimprovedhissexualdisturbanceorcausedanyworseningofhisanxiety.FinallywhenVenlafaxinewastrialedagainduetolackofeffectivealternativeswithno/littlesideeffects,thepatientcomplainedaboutfrequentsuicidethoughtsafteroneweekofVenlafaxineXR75mg.Othermedicationwasnotusedatthattime.Heappearedintheoutpatientclinicasveryanxious,reportedbeingafraidtostayonhisown,wasterrifiedthathemightlosecontrolandtounintentionallyharmhimself.Thesuicidalthoughtswereexperiencedinthesamewayasthesuicidalideationandsuicideattemptfromhisadolescentyears.AfterswitchingtoDuloxetine60mg/day,thesuicidalthoughtscompletelydisappeared.持续用帕罗西汀抗抑郁治疗4年后,患者开始述有射精延迟,这是由帕罗西汀导致的。因此,试用了其他抗抑郁药,这些药物均无法改善他的性功能障碍,但也没有导致焦虑加重。最后,由于没有无/很少副作用的有效替代药物,只能再次使用文拉法辛。用了文拉法辛XR75mg一周后,患者主诉经常出现自杀念头。当时没有用其他药物。他来门诊就诊时显得非常焦虑,据说不敢独处,害怕可能会失控并无意中伤害自己。此次的自杀念头出现的方式与青春期的自杀意念和自杀企图是一样的。将药物更换为度洛西汀60mg/天后,自杀念头完全消失。Discussion讨论Inthelastyears,severallargeretrospectiveanalyseswerecarriedoutinordertoexpandtheunderstandingofthephenomenonofsuicidalideationduetoSSRImedication.Thesestudiespointedoutthatregardingtheriskofdevelopingsuicideacts,thenewantidepressantspresentwithasimilarriskofsuicidalideationastheoldTCA,6,7.Itwasalsoconcludedthatantidepressantsasagroupelevatetheriskforsuicidecomparedtoplacebo8.过去几年中进行了几项大型回顾性分析,以加深对SSRI药物导致的自杀意念这一现象的了解。这些研究指出,对于发生自杀行为的风险,新型抗抑郁药导致的自杀意念风险与旧的三环类抗抑郁药(TCA)相当6,7。研究得出如下结论与安慰剂相比,所有抗抑郁药均会使自杀风险升高8。Ontheotherhand,manystudiesconfirmthereciprocalconnectionbetweentheincreaseduseofantidepressantsandthedeclineofsuicide.Forexample,inastudyconductedinScandinavia,victimsofsuicidewerecomparedtopeoplewhodiedasaresultofnaturalortraumaticevents.Thesuicidegroupwasrelativelyundertreatedwithantidepressants9.AmorerecentreportapplyingaggregateddatasuggeststhattheincreaseduseofSSRIsisrelatedtodecreasedsuiciderateswhereasTCAprescriptionswererelatedtoincreasedsuiciderates10.Onasimilarpoint,aretrospectiveanalysesoftherelationshipbetweenprescriptionsofSSRIsandsuicideratessuggeststhatthedecreaseofSSRIprescriptionsforchildrenandadolescents,bothintheUnitedStatesandtheNetherlands,afterU.S.andEuropeanregulatoryagenciesissuedwarningsaboutapossiblesuicideriskwithantidepressantuseinpediatricpatients,wasassociatedwithincreasesinsuicideratesinchildrenandadolescents11.另一方面,许多研究证实了抗抑郁药使用增多与自杀减少呈反相关。例如,在北欧进行的一项研究将自杀死亡者与自然死亡者或创伤事件死亡者进行比较。自杀组用抗抑郁药治疗相对不充分9。最近一份汇集了大量数据的报告表明,SSRI使用增多与自杀率下降有关,而TCA处方增多与自杀率上升有关10。与此相似的是,一项回顾SSRI处方与自杀率的联系的分析表明,自从美国和欧盟监管机构发布了儿科患者使用抗抑郁药有可能会发生自杀的警告以来,美国和荷兰儿童与青少年的SSRI处方减少与他们的自杀率上升有关11。Combiningthisresearchtheconclusionisthatforthesocietyasagroup,theuseofantidepressantsisbeneficial.Nevertheless,forcertainindividuals,thesemedicinescouldcausesuicideideationandputthemingreatrisk12.Therefore,identifyingthesepatientsisimportantfromaclinicalandlegalperspective.综上,该研究的结论是对于整个患者群体而言,使用抗抑郁药是有好处的。但是,对于某些个体,这些药物会导致自杀意念,使他们面临极大的危险12。因此,从临床和法律的角度来说,鉴定这些患者极为重要。Theraisingawarenessofthesuicidalriskfordevelopingsuicidalideationandbehaviorduringtreatmentwithantidepressantscausesadramaticchangeoftheattitudetowardthesedrugs.Thepresentedcasedemonstratesforthefirsttimearecurrenceofsuicidalityfollowingantidepressantsinpatientswithanxietydisorder.Therefore,suicidalityasadirectconsequenceofantidepressanttreatmentisnotrestrictedtopatientswithmajordepressivedisorder.Improvedunderstandingoftherisksanddetectionofearlyclinicalwarningsignswhileusingantidepressantsisthereforevitalforthesepatients.患者逐渐意识到用抗抑郁药治疗期间有出现自杀意念和行为的风险,因此他们对这些药物的态度发生了很大变化。本病例首次描述了焦虑症患者用抗抑郁药治疗后再次出现自杀意念。因此,自杀作为抗抑郁治疗的直接后果,并非只局限发生于重度抑郁症患者。因此,加深对使用抗抑郁药的风险的了解和发现自杀的早期临床先兆对这些患者很重要。Theunderstandingoftheprecisemechanismsbywhichantidepressantsmaycausesuicidalityisstilllacking.Fewtheorieswereputforwardalongtheyearsthatcanbedividedintotwogroupseitherattributedtodepressivesymptomsorattributedtothedrugitself.Theoriesaboutattributiontodepressivesymptomsclaimedthatthisphenomenonismerelyaconsequenceofaclinicalworseningofthespecificdisorderwhichisknownastheparadoxicalsuicide12,13.Othersspeculatedthatthesepatientsmaysufferfromanundiagnosedbipolardisorder14.Theoriesthatfocusonsideeffectofthedrugclaimedthatthedevelopmentofakathisiaduetoantidepressanttreatmentpossiblyisthecauseforsuicidality15.Beyondtheseexplanations,ourcasecontributestoothertheoriesasfollows.Idiosyncraticresponsetopsychotropicagentsmighthaveoccurredinbothsusceptibleindividualsassuicidalitysubsidedwhenswitchingtoanotherdrugofthesameclass.Thistheorygainsmorestrengthwhenconsideringthateventreatmentofnormalsubjectscouldresultinsuicideideation4.Furthermore,asuddenonsetofsuicidalfeelingsisawellknownbutstillrelativelyunderestimatedandnotwidelyunderstoodphenomenon.Patientsoftendescribefeelingsofhopelessnessanddespairthatmaydevelopafterstartingtreatmentwithanantidepressant12thatmayleadtosuicidality.Theclassicalactionofthereserpincanserveasamodelforsuchaction.Inaddition,autoaggressivefeelingsarepossiblypartofpanicattacksasreportedbyGeorgeetal.whodescribedthreepatientsdevelopingautoaggressiveandsuicidalthoughtduringpanicattacks16.Theauthorsdescribedthesuicidalideationassuddenattacksresemblingpanicattacks.目前,对抗抑郁药导致自杀的确切机制仍然知之甚少。这么多年来提出的一些理论可分为两类抑郁症状或药物本身导致自杀。认为抑郁症状导致自杀的理论声称这种现象只是特定疾病临床恶化的结果(称为矛盾性自杀)12,13。有人推测这些患者可能患有未被诊断出来的双相障碍14。关注药物副作用的理论认为抗抑郁治疗导致的静坐不能可能是自杀的原因15。除了上述两种解释,我们的病例还有如下理论当更换为另一种同类药物时,自杀念头消失,因此,对两种精神药物均敏感的患者对药物的反应可能会出现异质性。考虑到正常受试者用这些药物进行治疗也会产生自杀意念时,这种理论更有说服力4。此外,虽然突然出现自杀意念已经是一种众所周知的现象,但是仍然相对重视不够,且没有被广泛认识。开始用抗抑郁药治疗后可能出现会无助和绝望感12,患者常常会诉说这些可能导致自杀的感觉。利血平的经典效应可作为这种行为的模型。此外,George等报道自我攻击感可能是惊恐发作的一部分,他们描述了3名患者在惊恐发作时出现了自我攻击和自杀念头16。作者们描述的自杀意念是类似惊恐发作的突然攻击。Hypothetically,biologicalalterationsintheserotonergicsystemmighthavecontributedtothesuicidalideation/attemptinthepresenceofanSSRIwhereasthiseffectceasedwiththepureNSRIwasused.ThefollowingmechanismforareducedserotonergicactivityinducedbySSRIcanbesuggestedasanexplanationofourcaseobservation.Itisreportedthattheincreaseoftheconcentrationof5HTintheextracellularbrainspacethroughmostantidepressantsbypreventingitsreuptakeisoffsetbyanegativefeedbackoperatingatthe5HTcellbodylevel17.Itwasshownthattheinhibitionof5HTreuptakeproducedbyadministrationofSSRIscancauseamarkedenhancementoftheextracellularconcentrationof5HTinthemidbrainraphenuclei1820andaccountedforthesuppressionof5HTcellfiring21,22.Consequently,thepresenceofanSSRIcanleadtoareducedactivityofserotoninmediatedneuronalactivitypossiblerelatedtoabnormalbehavioursuchassuicidalideation.Unfortunately,sinceitwasnotpossibletoclarifythebiological/serotonergicmakeupofourcase,theseassumptionsrequirefurtherinvestigations.假设使用SSRI时,5羟色胺能系统的生物学改变会导致自杀意念/企图,而只用NSRI时这种效应消失。以下SSRI导致5羟色胺能活性降低的机制可被认为能够解释本病例观察到的现象。据报道,大多数抗抑郁药通过阻止5HT再摄取,使脑细胞外间隙的5HT浓度增加,但是5HT的细胞体水平可通过负反馈可抵消其浓度增加17。使用SSRI引起5HT再摄取被抑制可导致中脑中缝核的细胞外5HT浓度显著增加1820,还可抑制5HT细胞放电21,22。因此,SSRI可导致可能与自杀意念等异常行为有关的5HT介导的神经元活性降低。遗憾的是,由于无法阐明本病例的生物学/5羟色胺能成分,因此必须对这些假设进行进一步研究。Conclusion结论Nearlyallresearchonsuicideratesthatshowbiological23,psychological14,24andsocial25factorsthatcontributetosuiciderisk,donotdifferentiateexplicitlybetweenriskfordepressionandanxietydisorders.Morespecifically,littleattentionhasbeengiventoandnoclinicalexperiencereported,ifmodernantidepressantsdocontributetosuicideriskinanxietydisorders4.Moreclarityonthediagnosisspecificsuicideriskappearstobeimportantforclinicalpracticeandalsofortheunderstandingoftheunderlyingmechanismsofsuicideriskduetoantidepressants.Anenhancedunderstandingoftheanxietyspecificsuicideriskmighthelptoimproveclinicalpracticetoanticipateandearlyidentifyindividualsdevelopingsuicidalideationwhiletreatedwithantidepressants.几乎所有关于自杀率的研究都显示生物学23、心理14,24和社会25因素均可引起自杀,但没有明确区分抑郁症和焦虑症引起自杀的风险。更确切的说,目前甚少关注,也没有临床经验报道新型抗抑郁药是否有引起焦虑症患者自杀的风险4。更加清楚的阐明诊断特异性自杀风险似乎对临床实践和抗抑郁药导致的自杀风险的基础机制很重要。加深对焦虑特异性自杀风险的了解有助于改善临床实践,预测和早期鉴定用抗抑郁药治疗而出现自杀意念的个体。ConflictofinterestsTheauthorsdeclarethattheyhavenocompetinginterests.AuthorscontributionsDTwasthetreatingpsychiatristofthepatient.BothDTandBBdraftedthemanuscript,readandapprovedthefinalmanuscript.ConsentWritteninformedconsentwasobtainedfromthepatientforpublicationofthiscasereportandanyaccompanyingimages.AcopyofthewrittenconsentisavailableforreviewbytheEditorinChiefofthisjournal.AcknowledgementsWrittenconsentwasobtainedfromthepatientforpublicationofthestudy.References1.TeicherMH,GlodC,ColeJOEmergenceofintensesuicidalpreoccupationduringfluoxetinetreatment.AmJPsychiatry1990,1472207210.PubMedAbstract2.UKMedicinesandHealthCareProductsRegulatoryAgency,release.DHSeroxatmustnotbeusedfortreatmentofchildren.2003.3.AkiskalHS,BenazziFDoestheFDAproposedlistofpossiblecorrelatesofsuicidalityassociatedwithantidepressantsapplytoanadultprivatepracticepopulationJAffectDisord2006,9413105110.PubMedAbstract|PublisherFullText4.HealyDLinesofevidenceontherisksofsuicidewithselectiveserotoninreuptakeinhibitors.PsychotherPsychosom2003,7227179.PubMedAbstract|PublisherFullText5.APADiagnosticandStatisticalManualofMentalDisorders4thedDSMIV.1994.6.SimonGE,SavarinoJ,OperskalskiB,WangPSSuicideriskduringantidepressanttreatment.AmJPsychiatry2006,16314147.PubMedAbstract|PublisherFullText7.JickSS,DeanAD,JickHAntidepressantsandsuicide.Bmj1995,3106974215218.PubMedAbstract|PublisherFullText8.FergussonD,DoucetteS,GlassKC,ShapiroS,HealyD,HebertP,HuttonBAssociationbetweensuicideattemptsandselectiveserotoninreuptakeinhibitorssystematicreviewofrandomisedcontrolledtrials.Bmj2005,3307488396.PubMedAbstract|PublisherFullText|PubMedCentralFullText9.IsacssonG,HolmgrenP,AhlnerJSelectiveserotoninreuptakeinhibitorantidepressantsandtheriskofsuicideacontrolledforensicdatabasestudyof14,857suicides.ActaPsychiatrScand2005,1114286290.PubMedAbstract|PublisherFullText10.GibbonsRD,HurK,BhaumikDK,MannJJTherelationshipbetweenantidepressantmedicationuseandrateofsuicide.ArchGenPsychiatry2005,622165172.PubMedAbstract|PublisherF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