北醫(yī)藥物治療學(xué)抗抑郁藥課件

Depression王天晟,Pharm.D.,R.Ph.北京大學(xué)藥學(xué)院Depression王天晟,Pharm.D.,R.Ph.AdditionalResources:1.MannJJ.TheMedicalManagementofDepression.NewEnglandJournalofMedicine2005;353:1819-342.GelenbergAJ,HopkinsHS.AssessingandTreatingDepressioninPrimaryCareMedicine.AmericanJournalofMedicine.2007;120:105-1083.TheTexasImplementationofMedicationAlgorithms:UpdatetotheAlgorithmsforTreatmentofBipolarIDisorder.SuppesT.,etal.JournalofClinicalPsychiatry2005;66:870-886AdditionalResources:NeurotransmitterNeurotransmitter北醫(yī)藥物治療學(xué)抗抑郁藥課件synthesizingpackagingreleasingbindingremovalsynthesizingEpidemiologyoccursin1in8individualsduringtheirlifetime2-3%ofmales;5-9%offemalescomorbidities:anxietyimpulsecontroldisordersubstanceabuseAverageOnset:mid-20s,butcanmanifestatanyageEpidemiologyoccursin1in8iEpidemiologytriggeringfactors:deathoflovedone,divorce,chronicmedicalconditionsendocrinedisorder:Cushing’sdz,Addison’sdz,....Implication:>50%ofcompletedsuicidesinvolvedepressionannualcost:$44billionEpidemiologytriggeringfactorsEpidemiologyCourseofillnesssingleepisoderecurrentepisodes60%ofPtsw/singleepisode:developa2ndepisodePtsw/2ndepisode:70%chanceofhavinga3rdepisodePtsw/3rdepisode:90%chanceofhavinga4thepisodeEpidemiologyCourseofillnessEpidemiology5-10%ofPtsw/singledepressiveepisode:willeventuallyexperiencemanicepisodePsw/residualsymptomsmorelikelytosufferfromfuturedepressiveepisodesEpidemiology5-10%ofPtsw/siPathophysiologyexactetiologyunknownmostlikelymultifactorial:genetic,environmental,biological1stdegreerelativew/depression1.5-3timesmorelikelytodevelopbrainimaginghasidentifiednumerousregionsofalteredstructureactivityPathophysiologyexactetiologyPathophysiologyPositronEmissionTomography(PET)studies↓in5-HTtransportersalteredpost-synaptic5-HT-receptorbindingPtssufferingw/depressionbrain5-HTandNElevels:DONOTdifferfromcontrols↑5-HTandNEtransmission:DOEStreatsymptoms.PathophysiologyPositronEmissiDiagnosisdepressedmoodlackofinterest/pleasurealmostdaily≥2weeks.alsomusthave≥4additionalsymptoms(SIGECAPS)DiagnosisdepressedmoodDiagnosisSIGECAPS:mustbeaccompaniedbysignificantimpairmentinfunctioning.cannotbeduetoeffectsofsubstanceabuse,drugsideeffect,toxinexposurebereavement(within2monthsofloss).DiagnosisSIGECAPS:北醫(yī)藥物治療學(xué)抗抑郁藥課件GeneralTreatmentPrinciplesGeneralTreatmentPrinciplesDurationofUse所有ADs需要≥4周治療(最好8周)@足夠劑量治療劑量持續(xù)6-9個(gè)月,更多建議為12個(gè)月維持治療≥2年:針對復(fù)發(fā)/慢性抑郁候選患者：≥3episodesofmajordepression≥2episodes+≥1ofthefollowing:*情緒障礙家族史，快速復(fù)發(fā)，年老/嚴(yán)重發(fā)作維持治療=同樣藥物/同樣劑量DurationofUse所有ADs需要≥4周治療(最北醫(yī)藥物治療學(xué)抗抑郁藥課件ResponseResponse:≥50%↓insymptoms50%ofPtswillstillhaveresidualsymptomsPredictorsofresponseabsenceofneurovegetativesymptomspastresponsefamilialresponsepatientsadherencewithvisitsandmedsResponseResponse:≥50%↓insym6-12weeks4-9months≥1yearResponsevs.Remission6-12weeks4-9months≥1yearResDiscontinuation/Withdrawalsyndrome戒斷癥狀vividdreams,惡夢,顫動(dòng),頭暈,頭痛,電休克感,惡心不建議立即停藥,(逐漸減小劑量≥7-10天）例外：氟西汀(Fluoxetine)Discontinuation/WithdrawalsynSuicidalitySuicidalityBlackBoxWarning:↑<25歲患者自殺風(fēng)險(xiǎn)@治療的第一個(gè)月自殺風(fēng)險(xiǎn)：無治療>治療IntroductionofFluoxtineandotherADsinlate1980sBlackBoxWarning:↑<25歲患者自殺風(fēng)險(xiǎn)SerotoninSyndrome惶惑煩躁不安肌陣攣反射亢進(jìn)出汗顫動(dòng)顫抖痢疾輕度狂躁不協(xié)調(diào)性...SerotoninSyndrome惶惑SerotoninSyndrome5-HT綜合征(5-HTstorm)可以↑5-HT水平的藥物都有此風(fēng)險(xiǎn)veryrare,<1%,especiallywithmonotherapy兩種↑5-HT藥物合用時(shí)風(fēng)險(xiǎn)↑c(diǎn)anbelifethreateningSerotoninSyndrome5-HT綜合征(5-HVideoVideoAntidepressants(ADs)Antidepressants(ADs)TricyclicAntidepressants三環(huán)類(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)丙咪嗪(imipramine)desipramineclomipramineTricyclicAntidepressants三環(huán)類(TCAs1線用藥：1960s-1980s不同程度上阻斷NE和5HT重吸收TCAs1線用藥：1960s-1980sTCAs“dirtyreceptorbinding”:同時(shí)阻斷其他受體組胺膽堿alpha腎上腺素肝代謝劑量：largeinterpatientpharmacokineticvariability,serumlevelsplayalargeroleindeterminingdoseTCAs“dirtyreceptorbinding”:Disadvantages抗膽堿(anticholinergic)副作用口干燥視力模糊尿潴留便秘中樞神經(jīng)(激動(dòng)、錯(cuò)覺、煩躁不安)Desipramine&去甲替林(nortriptyline):lessanticholinergic通常不用于老年患者Disadvantages抗膽堿(anticholinergDisadvantages心血管副作用:最好避免用于潛在心血管疾病患者直立性低血壓心跳加速傳導(dǎo)延時(shí)5-HT副作用增加癲癇發(fā)作的可能性轉(zhuǎn)換為狂躁:≤10%ofpatientscanswitchrapidly過量劑量可致命Disadvantages心血管副作用:最好避免用于潛在心Advantages廉價(jià)longtrackrecordplasmalevelsareusefulinmonitoring也可用于治療疼痛、焦慮、失眠，預(yù)防偏頭痛Advantages廉價(jià)SelectiveSerotoninReuptakeInhibitors選擇性5-HT再攝取抑制劑(SSRIs)氟西汀(fluoxetine)帕羅西汀(paroxetine)舍曲林(sertraline)西酞普蘭(citalopram)艾司西酞普蘭(escitalopram)fluvoxamineSelectiveSerotoninReuptakeIMOA抑制5-HT在突出的重吸收對組胺、膽堿、或腎上腺素受體無吸引力5-HT1A=antidepressantaction5-HT2&5-HT3=胃腸和性功能副作用MOA抑制5-HT在突出的重吸收TreatmentofChoiceAdvantagesoverTCAs過量劑量不會(huì)致命鎮(zhèn)靜作用更少體重增加更少無心血管副作用心臟傳導(dǎo)改變直立性低血壓尿潴留TreatmentofChoiceAdvantagesTreatmentofChoiceeffectiveforseveralcomorbiditesaswell廣泛性焦慮癥社交恐懼癥強(qiáng)迫癥貪食,經(jīng)前期煩躁不安的紊亂血漿濃度和臨床效果無關(guān)給藥:每日一次TreatmentofChoiceeffectivef5-HTSideeffectsEarlyonset惡心:特別是舍曲林(sertraline),1-2星期產(chǎn)生耐受性焦慮&激動(dòng):初始明顯，然后減弱，氟西汀(fluoxetine)&sertraline最明顯：5-HTSideeffectsEarlyonset5-HTSideeffectsLateonset失眠:初始可能鎮(zhèn)靜，特別是帕羅西汀(paroxetine)體重改變:初始可能體重↓，后期↑,特別是paroxetine性功能障礙:性欲↓，性快感↓，陽痿，特別是sertraline5-HTSideeffectsLateonsetInteractionsMAOI2星期清空期(washoutperiod),Fluoxetine需5星期fluoxetine→MAOIs:5weeksMAOIS→fluoxetine：2weeksInteractionsMAOIInteractions其他可能↑5-HT水平的藥物曲馬多(tramadol),哌替啶(meperidine),triptan,e.g.舒馬普坦(sumatriptan),rizatriptan...TCAs,SNRIothersduetocytochromeP450effects:e.g.fluoxetinemay↑c(diǎn)arbamazepine,alprazolam,phenytoinconcentrationsInteractions其他可能↑5-HT水平的藥物Dosing開始低劑量逐漸↑劑量：↑頻率小于每周(nosoonerthanweekly)4-6周后評價(jià)效果somesymptomsmayrespondin1-2weeksaimforremissionofsymptomsand/ortargetdoseDosing開始低劑量北醫(yī)藥物治療學(xué)抗抑郁藥課件Fluoxetinetreatresistant,急性治療現(xiàn)階段抑郁已用2個(gè)不同抗抑郁藥治療，足夠劑量,療程仍無效果必須與奧氮平(olanzapine)合用定期重新評估治療的必要性fluoxetine初始劑量:20mgqpm逐漸降低劑量停藥Fluoxetinetreatresistant,急性治Serotonin&NorepinephrineReuptakeInhibitors5-HT和NE雙重再攝取抑制劑(SNRIs)萬拉法新(venlafaxine)Des-venlafaxine杜洛西汀(duloxetine)Serotonin&NorepinephrineReuMOAofSNRIs“dual-acting”ADs:NE&5-HT→maybeeffectiveinPtswho’vefailedSSRIsbutlittleevidencetosupportadifferenceMOAofSNRIs“dual-acting”ADs:Venlafaxinedose<200mgqd=5-HTreuptakeprimarily>200mgqd=5-HT&NEreuptakeXRformulationpreferredAdvantage幾乎無直立性低血壓副作用P450酶的弱抑制劑VenlafaxinedoseVenlafaxineDisadvantage:common“5-HTsideeffect”1.惡心2.嗜睡，失眠3.厭食4.性功能障礙可能↑舒張壓:監(jiān)控血壓戒斷癥狀顯著VenlafaxineDisadvantage:DesvanlafaxineFDAapprovalFebruary2008activemetaboliteofVenlafaxineDesvanlafaxineFDAapprovalFebDuloxetine5-HT&NEreuptakeinhibitorthroughentiredoserange可治療神經(jīng)痛和其他慢性疼痛longtermstudiesindicatelowpotentialforweight↑mayhavelesssexualdysfunctionthanSSRIs副作用common5-HTsideeffects直立性低血壓lowerriskofBP↑vs.venlafaxineDuloxetine5-HT&NEreuptakei2ndGenerationADs第2代抗抑郁安菲他酮(bupropion)米氮平(mirtazapine)nefazodone2ndGenerationADs第2代抗抑郁Bupropion抑制NE和DA的重吸收multipledoseformulations:IR,SR,XLIR=upto150mgperdose:100mgtidSR=upto200mgperdose:100mgbidXL=upto450mgperdose:300mgqamBupropion抑制NE和DA的重吸收BupropionAdvantagesnotassociatedwithrapidcycling性功能障礙概率低體重↑很少無抗膽堿副作用可用于戒煙治療Disadvantagessideeffects激活效應(yīng)：失眠,焦慮顫動(dòng)↑癲癇可能性禁用于癲癇,飲食失調(diào),酒精戒斷BupropionAdvantagesMirtazapine↑serotonergictransmission阻斷5-HT2A,5-HT2C,&5-HT3受體potentH1antagonistMirtazapine↑serotonergictranMirtazapineAdvantagesT1/2=20-40hours,QD藥物相互作用最少無性功能障礙副作用胃腸道副作用<SSRIssedationmaybehelpfulDisadvantages體重↑鎮(zhèn)靜riskof↑c(diǎn)holesterol“zapine”MirtazapineAdvantagesNefazodoneblocks5-HT2receptorinhibits5-HTreuptakerarelyusedduetoblack-boxwarninglife-threateninghepaticfailureNefazodoneblocks5-HT2receptoMonoamineOxidaseInhibitors單胺氧化酶抑制劑(MAOIs)phenelzinetranylcypromine司來吉蘭(selegiline)MonoamineOxidaseInhibitors單胺MAOIs抑制單胺氧化酶breakdownofNE,5-HT,&DAisinhibitedbreakdownoftyramine(酪胺)isinhibitedmonoaminecompoundderivedfromaminoacidtyrosineeffectsofdrugslast14dayswithirreversibleinhibitorsUse=非典型/復(fù)發(fā)性抑郁MAOIs抑制單胺氧化酶SideEffects直立性低血壓體重↑失眠、不安性功能障礙高血壓危象：withtyraminecontainingfoods,pressors枕骨頭痛，頸部僵直↑BP,心悸惡心/嘔吐，出汗SideEffects直立性低血壓Interactions=numerous哌替啶(meperidine):高燒，高血壓，昏迷Sympathomimetics:especiallyindirectRx:安非他明(amphetamine),右旋安非他明(dextroamphetamine),哌甲酯(methylphenidate)OTCdecongestant:偽麻黃堿(pseudoephedrine),去氧腎上腺素(phenylephrine)SSRIs&其他抗抑郁藥:5-HT綜合征dietInteractions=numerous哌替啶(mepSelegiline司來吉蘭(selegiline)PO:MAO-Bselective(primarily↑DA)透皮(transdermal)bypasses1stpassmetabolismallowshigherCNSconcentrationsbypassesintestinalinhibitionofMAO-A*noneedfortyramine-freediet@6mgqd(initial)doseSelegiline司來吉蘭(selegiline)AugmentationOptionsinTreatmentofDepressionAugmentationOptionsinTreatmLithium(鋰):treatbipolar,mania,schizoaffectived/oThyroidhomone(甲狀腺激素)Buspirone(丁螺環(huán)酮):treatanxietyAtypicalAntipsychotics:aripiprazole(阿立哌唑)PsychostimulantDrugs:dextroamphetamine/amphetamineLithium(鋰):treatbipolar,manNonpharmacologicTreatmentofDepressionNonpharmacologicTreatmentofECT(electrocompulsivetreatment)mosteffectTxforMDD(95%)PhototherapyespeciallyforseasonalaffectivedisorderrTMS(repetitiveTranscranialMagneticStimulation)ECT(electrocompulsivetreatmeChoiceofAntidepressantChoiceofAntidepressant非復(fù)雜的單相抑郁:所有抗抑郁藥視為等效exceptions:(levelofevidenceisnotgreat)TCAsclearlyefficaciousinseveredepressionbupropionmaytheoreticallyworkwellinPtsw/apathyvenlafaxinemaybemoreeffectiveinTx-resistantdepressionthanSSRIsMAOIsparticularlyeffectiveforPtswithatypicalfeatures(SSRIsalsoshowpromise)某類藥物中某個(gè)藥物無效≠該類藥物中其他藥物無效!非復(fù)雜的單相抑郁:所有抗抑郁藥視為等效ChoiceamongAgentsbasedon...ChoiceamongAgentsbasedon..1.Sideeffect1.Sideeffect2.PotentialforInteraction2.PotentialforInteraction3.安全性?年齡，過量用藥風(fēng)險(xiǎn)，懷孕等fluoxetine:mostdata,still“C”paroxetine,“D”4.患者傾向5.患者對過去治療的反應(yīng)6.費(fèi)用3.安全性?SequencedTreatmentAlternativestoResolveDepression7yeartrialfundedbyNIMH,4041patientsDesignedRandomizationusedtocomparevariousswitchingoraugmentingstrategieseithercommonlyusedorthatarebasedonpharmacologicreasoning(12weeksperlevel)*STAR*DTrialSequencedTreatmentAlternativLEVEL1INITIALTREATMENT:西酞普蘭(Citalopram)LEVEL2SWITCHTO:安菲他酮(Bupropion)(sustainedrelease,SR),cognitivetherapy,舍曲林(Sertraline),文拉法辛(Venlafaxine)(extended-release,ER)ORAUGMENTWITH:Bupropionsustainedrelease,丁螺環(huán)酮(Buspirone),cognitivetherapyLEVEL2A(OnlyforthosereceivingcognitivetherapyinLevel2)SWITCHTO:BupropionSRorVenlafaxineERLEVEL3SWITCHTO:米氮平(Mirtazapine)or去甲替林(Nortriptyline)ORAUGMENTWITH:LithiumorTriiodothyronine(onlywithBupropionSR,Sertraline,VenlafaxineERLEVEL4SWITCHTO:TranylcypromineorMirtazapinecombinedwithVenlafaxineERLEVEL1INITIALTREATMENT:西酞Atlevel1?~30%remission;47%responsewithcitalopramInPtsfailtoobtainadequatebenefitfrom≥2treatmenttrialsonlymodestresponsescanbeexpectedfromeachsubsequenttreatmenttrial.AfterseveralpreviousantidepressanttrialsT3moretolerableandeasiertousethanlithiumAftermultiplefailedtrials,Venlafaxine+MirtazapineispreferredoverTranylcypromineConclusionAtlevel1?~30%remission;47%C11:AG,36歲女性,抑郁已有2個(gè)月，性生活質(zhì)量下降，食欲和體重增加，嗜睡嚴(yán)重，有自殺傾向。實(shí)習(xí)醫(yī)生建議用阿米替林(amitriptyline)，藥師的用藥方案？C12:SW,27歲男性，失業(yè)已有半年，吸煙，接受抑郁治療，西酞普蘭(citalopram)20mg/d已有2星期，患者抱怨“藥物不起作用”，希望醫(yī)生換藥，藥師建議的用藥方案？C13:GW,36歲男性，大學(xué)教師，接受氟西汀(fluoxetine)40mgqam治療抑郁9個(gè)月，效果不加，醫(yī)生決定換藥，使用司來吉蘭(selegiline),藥師建議用藥方案？C14:KB,36歲女性，由于自殺傾向和大量吞服藥物入院。KB過去2個(gè)月中情緒嚴(yán)重低落，由于長時(shí)間加班導(dǎo)致很大的工作壓力。KB想多花時(shí)間和家人在一起，覺得自己“讓丈夫和孩子失望”。KB過去3年中因伴隨自殺傾向的抑郁癥住院2次，曾先后接受安菲他酮(buprobion)和西酞普蘭(citalopram)較高劑量和足夠療程治療重度抑郁，但效果不佳。正在服用的藥物：citalopram60mgqd,simvastatin20mgqhs,Zolpidem10mgHSprn.藥師建議的抑郁治療方案？C15,LB,41歲男性，接受抑郁治療帕羅西汀(paroxetine)20mg/d12個(gè)星期后回到藥房取藥，告訴藥師LB自己感覺心情不錯(cuò)，睡眠也像過去一樣不錯(cuò)。然后又和藥師低聲說最近開始性功能障礙，不知是否和該藥引起，如果是，LB要求換藥。此時(shí)藥師向醫(yī)生建議的用藥方案？C11:AG,36歲女性,抑郁已有2個(gè)月，性生活質(zhì)量下C16:AK,48歲男性，因中度抑郁住院，這是他去年以來的第3次抑郁發(fā)作。正服用舍曲林(sertraline)150mgqd.他妻子說AK經(jīng)常連續(xù)3，4天沒有服藥，由于需要因?yàn)楣ぷ髀眯袝r(shí)忘記了攜帶藥品。AK成人這種時(shí)候自己會(huì)變得非常憂慮，而且經(jīng)常覺得惡心。為解決AK依從性差的問題，藥師向醫(yī)生建議的用藥方案是？C17:RH,19歲女性，服用帕羅西汀(paroxetine)40mgqd.她抱怨該藥帶來過多嗜睡癥狀，要求換另外一種抗抑郁藥。她過去疾病史包括腸易激綜合征，經(jīng)常惡心，甲狀腺功能減退癥，最近由于飲食失調(diào)住院。醫(yī)生的處方是:安菲他酮(Bupropion)100mgbid,3天后增加劑量。藥師看到處方后的建議？C18：WH,31歲女演員,服用丙咪嗪(imipramine)治療抑郁，抱怨體重增加和身材走樣，要求醫(yī)生換藥。藥師給醫(yī)生建議的用藥方案為？C19：AO,60歲男性，抑郁癥同時(shí)有慢性疼痛。正服用的藥物有：地高辛(digoxin)1mgqd,lisinopril40mg/d，藥師建議的用藥方案？C20：AK，26歲男性，接受西酞普蘭(citalopram)40mgqd治療抑郁效果不佳，嘗試過帕羅西汀(paroxetine),舍曲林(sertraline),和萬拉法新(venlafaxine),藥師建議？C21：JT,37歲女性，互聯(lián)網(wǎng)公司CEO,年初開始失眠，服用安定已有5個(gè)月。因公司業(yè)績問題，工作壓力大等原因患抑郁癥，藥師建議的用藥方案?C16:AK,48歲男性，因中度抑郁住院，這是他去年以來Thankyou.Thankyou.Depression王天晟,Pharm.D.,R.Ph.北京大學(xué)藥學(xué)院Depression王天晟,Pharm.D.,R.Ph.AdditionalResources:1.MannJJ.TheMedicalManagementofDepression.NewEnglandJournalofMedicine2005;353:1819-342.GelenbergAJ,HopkinsHS.AssessingandTreatingDepressioninPrimaryCareMedicine.AmericanJournalofMedicine.2007;120:105-1083.TheTexasImplementationofMedicationAlgorithms:UpdatetotheAlgorithmsforTreatmentofBipolarIDisorder.SuppesT.,etal.JournalofClinicalPsychiatry2005;66:870-886AdditionalResources:NeurotransmitterNeurotransmitter北醫(yī)藥物治療學(xué)抗抑郁藥課件synthesizingpackagingreleasingbindingremovalsynthesizingEpidemiologyoccursin1in8individualsduringtheirlifetime2-3%ofmales;5-9%offemalescomorbidities:anxietyimpulsecontroldisordersubstanceabuseAverageOnset:mid-20s,butcanmanifestatanyageEpidemiologyoccursin1in8iEpidemiologytriggeringfactors:deathoflovedone,divorce,chronicmedicalconditionsendocrinedisorder:Cushing’sdz,Addison’sdz,....Implication:>50%ofcompletedsuicidesinvolvedepressionannualcost:$44billionEpidemiologytriggeringfactorsEpidemiologyCourseofillnesssingleepisoderecurrentepisodes60%ofPtsw/singleepisode:developa2ndepisodePtsw/2ndepisode:70%chanceofhavinga3rdepisodePtsw/3rdepisode:90%chanceofhavinga4thepisodeEpidemiologyCourseofillnessEpidemiology5-10%ofPtsw/singledepressiveepisode:willeventuallyexperiencemanicepisodePsw/residualsymptomsmorelikelytosufferfromfuturedepressiveepisodesEpidemiology5-10%ofPtsw/siPathophysiologyexactetiologyunknownmostlikelymultifactorial:genetic,environmental,biological1stdegreerelativew/depression1.5-3timesmorelikelytodevelopbrainimaginghasidentifiednumerousregionsofalteredstructureactivityPathophysiologyexactetiologyPathophysiologyPositronEmissionTomography(PET)studies↓in5-HTtransportersalteredpost-synaptic5-HT-receptorbindingPtssufferingw/depressionbrain5-HTandNElevels:DONOTdifferfromcontrols↑5-HTandNEtransmission:DOEStreatsymptoms.PathophysiologyPositronEmissiDiagnosisdepressedmoodlackofinterest/pleasurealmostdaily≥2weeks.alsomusthave≥4additionalsymptoms(SIGECAPS)DiagnosisdepressedmoodDiagnosisSIGECAPS:mustbeaccompaniedbysignificantimpairmentinfunctioning.cannotbeduetoeffectsofsubstanceabuse,drugsideeffect,toxinexposurebereavement(within2monthsofloss).DiagnosisSIGECAPS:北醫(yī)藥物治療學(xué)抗抑郁藥課件GeneralTreatmentPrinciplesGeneralTreatmentPrinciplesDurationofUse所有ADs需要≥4周治療(最好8周)@足夠劑量治療劑量持續(xù)6-9個(gè)月,更多建議為12個(gè)月維持治療≥2年:針對復(fù)發(fā)/慢性抑郁候選患者：≥3episodesofmajordepression≥2episodes+≥1ofthefollowing:*情緒障礙家族史，快速復(fù)發(fā)，年老/嚴(yán)重發(fā)作維持治療=同樣藥物/同樣劑量DurationofUse所有ADs需要≥4周治療(最北醫(yī)藥物治療學(xué)抗抑郁藥課件ResponseResponse:≥50%↓insymptoms50%ofPtswillstillhaveresidualsymptomsPredictorsofresponseabsenceofneurovegetativesymptomspastresponsefamilialresponsepatientsadherencewithvisitsandmedsResponseResponse:≥50%↓insym6-12weeks4-9months≥1yearResponsevs.Remission6-12weeks4-9months≥1yearResDiscontinuation/Withdrawalsyndrome戒斷癥狀vividdreams,惡夢,顫動(dòng),頭暈,頭痛,電休克感,惡心不建議立即停藥,(逐漸減小劑量≥7-10天）例外：氟西汀(Fluoxetine)Discontinuation/WithdrawalsynSuicidalitySuicidalityBlackBoxWarning:↑<25歲患者自殺風(fēng)險(xiǎn)@治療的第一個(gè)月自殺風(fēng)險(xiǎn)：無治療>治療IntroductionofFluoxtineandotherADsinlate1980sBlackBoxWarning:↑<25歲患者自殺風(fēng)險(xiǎn)SerotoninSyndrome惶惑煩躁不安肌陣攣反射亢進(jìn)出汗顫動(dòng)顫抖痢疾輕度狂躁不協(xié)調(diào)性...SerotoninSyndrome惶惑SerotoninSyndrome5-HT綜合征(5-HTstorm)可以↑5-HT水平的藥物都有此風(fēng)險(xiǎn)veryrare,<1%,especiallywithmonotherapy兩種↑5-HT藥物合用時(shí)風(fēng)險(xiǎn)↑c(diǎn)anbelifethreateningSerotoninSyndrome5-HT綜合征(5-HVideoVideoAntidepressants(ADs)Antidepressants(ADs)TricyclicAntidepressants三環(huán)類(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)丙咪嗪(imipramine)desipramineclomipramineTricyclicAntidepressants三環(huán)類(TCAs1線用藥：1960s-1980s不同程度上阻斷NE和5HT重吸收TCAs1線用藥：1960s-1980sTCAs“dirtyreceptorbinding”:同時(shí)阻斷其他受體組胺膽堿alpha腎上腺素肝代謝劑量：largeinterpatientpharmacokineticvariability,serumlevelsplayalargeroleindeterminingdoseTCAs“dirtyreceptorbinding”:Disadvantages抗膽堿(anticholinergic)副作用口干燥視力模糊尿潴留便秘中樞神經(jīng)(激動(dòng)、錯(cuò)覺、煩躁不安)Desipramine&去甲替林(nortriptyline):lessanticholinergic通常不用于老年患者Disadvantages抗膽堿(anticholinergDisadvantages心血管副作用:最好避免用于潛在心血管疾病患者直立性低血壓心跳加速傳導(dǎo)延時(shí)5-HT副作用增加癲癇發(fā)作的可能性轉(zhuǎn)換為狂躁:≤10%ofpatientscanswitchrapidly過量劑量可致命Disadvantages心血管副作用:最好避免用于潛在心Advantages廉價(jià)longtrackrecordplasmalevelsareusefulinmonitoring也可用于治療疼痛、焦慮、失眠，預(yù)防偏頭痛Advantages廉價(jià)SelectiveSerotoninReuptakeInhibitors選擇性5-HT再攝取抑制劑(SSRIs)氟西汀(fluoxetine)帕羅西汀(paroxetine)舍曲林(sertraline)西酞普蘭(citalopram)艾司西酞普蘭(escitalopram)fluvoxamineSelectiveSerotoninReuptakeIMOA抑制5-HT在突出的重吸收對組胺、膽堿、或腎上腺素受體無吸引力5-HT1A=antidepressantaction5-HT2&5-HT3=胃腸和性功能副作用MOA抑制5-HT在突出的重吸收TreatmentofChoiceAdvantagesoverTCAs過量劑量不會(huì)致命鎮(zhèn)靜作用更少體重增加更少無心血管副作用心臟傳導(dǎo)改變直立性低血壓尿潴留TreatmentofChoiceAdvantagesTreatmentofChoiceeffectiveforseveralcomorbiditesaswell廣泛性焦慮癥社交恐懼癥強(qiáng)迫癥貪食,經(jīng)前期煩躁不安的紊亂血漿濃度和臨床效果無關(guān)給藥:每日一次TreatmentofChoiceeffectivef5-HTSideeffectsEarlyonset惡心:特別是舍曲林(sertraline),1-2星期產(chǎn)生耐受性焦慮&激動(dòng):初始明顯，然后減弱，氟西汀(fluoxetine)&sertraline最明顯：5-HTSideeffectsEarlyonset5-HTSideeffectsLateonset失眠:初始可能鎮(zhèn)靜，特別是帕羅西汀(paroxetine)體重改變:初始可能體重↓，后期↑,特別是paroxetine性功能障礙:性欲↓，性快感↓，陽痿，特別是sertraline5-HTSideeffectsLateonsetInteractionsMAOI2星期清空期(washoutperiod),Fluoxetine需5星期fluoxetine→MAOIs:5weeksMAOIS→fluoxetine：2weeksInteractionsMAOIInteractions其他可能↑5-HT水平的藥物曲馬多(tramadol),哌替啶(meperidine),triptan,e.g.舒馬普坦(sumatriptan),rizatriptan...TCAs,SNRIothersduetocytochromeP450effects:e.g.fluoxetinemay↑c(diǎn)arbamazepine,alprazolam,phenytoinconcentrationsInteractions其他可能↑5-HT水平的藥物Dosing開始低劑量逐漸↑劑量：↑頻率小于每周(nosoonerthanweekly)4-6周后評價(jià)效果somesymptomsmayrespondin1-2weeksaimforremissionofsymptomsand/ortargetdoseDosing開始低劑量北醫(yī)藥物治療學(xué)抗抑郁藥課件Fluoxetinetreatresistant,急性治療現(xiàn)階段抑郁已用2個(gè)不同抗抑郁藥治療，足夠劑量,療程仍無效果必須與奧氮平(olanzapine)合用定期重新評估治療的必要性fluoxetine初始劑量:20mgqpm逐漸降低劑量停藥Fluoxetinetreatresistant,急性治Serotonin&NorepinephrineReuptakeInhibitors5-HT和NE雙重再攝取抑制劑(SNRIs)萬拉法新(venlafaxine)Des-venlafaxine杜洛西汀(duloxetine)Serotonin&NorepinephrineReuMOAofSNRIs“dual-acting”ADs:NE&5-HT→maybeeffectiveinPtswho’vefailedSSRIsbutlittleevidencetosupportadifferenceMOAofSNRIs“dual-acting”ADs:Venlafaxinedose<200mgqd=5-HTreuptakeprimarily>200mgqd=5-HT&NEreuptakeXRformulationpreferredAdvantage幾乎無直立性低血壓副作用P450酶的弱抑制劑VenlafaxinedoseVenlafaxineDisadvantage:common“5-HTsideeffect”1.惡心2.嗜睡，失眠3.厭食4.性功能障礙可能↑舒張壓:監(jiān)控血壓戒斷癥狀顯著VenlafaxineDisadvantage:DesvanlafaxineFDAapprovalFebruary2008activemetaboliteofVenlafaxineDesvanlafaxineFDAapprovalFebDuloxetine5-HT&NEreuptakeinhibitorthroughentiredoserange可治療神經(jīng)痛和其他慢性疼痛longtermstudiesindicatelowpotentialforweight↑mayhavelesssexualdysfunctionthanSSRIs副作用common5-HTsideeffects直立性低血壓lowerriskofBP↑vs.venlafaxineDuloxetine5-HT&NEreuptakei2ndGenerationADs第2代抗抑郁安菲他酮(bupropion)米氮平(mirtazapine)nefazodone2ndGenerationADs第2代抗抑郁Bupropion抑制NE和DA的重吸收multipledoseformulations:IR,SR,XLIR=upto150mgperdose:100mgtidSR=upto200mgperdose:100mgbidXL=upto450mgperdose:300mgqamBupropion抑制NE和DA的重吸收BupropionAdvantagesnotassociatedwithrapidcycling性功能障礙概率低體重↑很少無抗膽堿副作用可用于戒煙治療Disadvantagessideeffects激活效應(yīng)：失眠,焦慮顫動(dòng)↑癲癇可能性禁用于癲癇,飲食失調(diào),酒精戒斷BupropionAdvantagesMirtazapine↑serotonergictransmission阻斷5-HT2A,5-HT2C,&5-HT3受體potentH1antagonistMirtazapine↑serotonergictranMirtazapineAdvantagesT1/2=20-40hours,QD藥物相互作用最少無性功能障礙副作用胃腸道副作用<SSRIssedationmaybehelpfulDisadvantages體重↑鎮(zhèn)靜riskof↑c(diǎn)holesterol“zapine”MirtazapineAdvantagesNefazodoneblocks5-HT2receptorinhibits5-HTreuptakerarelyusedduetoblack-boxwarninglife-threateninghepaticfailureNefazodoneblocks5-HT2receptoMonoamineOxidaseInhibitors單胺氧化酶抑制劑(MAOIs)phenelzinetranylcypromine司來吉蘭(selegiline)MonoamineOxidaseInhibitors單胺MAOIs抑制單胺氧化酶breakdownofNE,5-HT,&DAisinhibitedbreakdownoftyramine(酪胺)isinhibitedmonoaminecompoundderivedfromaminoacidtyrosineeffectsofdrugslast14dayswithirreversibleinhibitorsUse=非典型/復(fù)發(fā)性抑郁MAOIs抑制單胺氧化酶SideEffects直立性低血壓體重↑失眠、不安性功能障礙高血壓危象：withtyraminecontainingfoods,pressors枕骨頭痛，頸部僵直↑BP,心悸惡心/嘔吐，出汗SideEffects直立性低血壓Interactions=numerous哌替啶(meperidine):高燒，高血壓，昏迷Sympathomimetics:especiallyindirectRx:安非他明(amphetamine),右旋安非他明(dextroamphetamine),哌甲酯(methylphenidate)OTCdecongestant:偽麻黃堿(pseudoephedrine),去氧腎上腺素(phenylephrine)SSRIs&其他抗抑郁藥:5-HT綜合征dietInteractions=numerous哌替啶(mepSelegiline司來吉蘭(selegiline)PO:MAO-Bselective(primarily↑DA)透皮(transdermal)bypasses1stpassmetabolismallowshigherCNSconcentrationsbypassesintestinalinhibitionofMAO-A*noneedfortyramine-freediet@6mgqd(initial)doseSelegiline司來吉蘭(selegiline)AugmentationOptionsinTreatmentofDepressionAugmentationOptionsinTreatmLithium(鋰):treatbipolar,mania,schizoaffectived/oThyroidhomone(甲狀腺激素)Buspirone(丁螺環(huán)酮):treatanxietyAtypicalAntipsychotics:aripiprazole(阿立哌唑)PsychostimulantDrugs:dextroamphetamine/amphetamineLithium(鋰):treatbipolar,manNonpharmacologicTreatmentofDepressionNonpharmacologicTreatmentofECT(electrocompulsivetreatment)mosteffectTxforMDD(95%)PhototherapyespeciallyforseasonalaffectivedisorderrTMS(repetitiveTranscranialMagneticStimulation)ECT(electrocompulsivetreatmeChoiceofAntidepressantChoiceofAntidepressant非復(fù)雜的單相抑郁:所有抗抑郁藥視為等效exceptions:(levelofevidenceisnotgreat)TCAsclearlyefficaciousinseveredepressionbupropionmaytheoreticallyworkwellinPtsw/apathyvenlafaxinemaybemoreeffectiveinTx-resistantdepressionthanSSRIsMAOIsparticularlyeffectiveforPtswithatypicalfeatures(SSRIsalsoshowpromise)某類藥物中某個(gè)藥物無效≠該類藥物中其他藥物無效!非復(fù)雜的單相抑郁:所有抗抑郁藥視為等效ChoiceamongAgentsbasedon...ChoiceamongAgentsbasedon..1.Sideeffect1.Sideeffect2.PotentialforInteraction2.PotentialforInteraction3.安全性?年齡，過量用藥風(fēng)險(xiǎn)，懷孕等fluoxetine:mostdata,still“C”paroxetine,“D”4.患者傾向5.患者對過去治療的反應(yīng)6.費(fèi)用3.安全性?SequencedTreatmentAlternativestoResolveDepression7yeartrialfundedbyNIMH,4041patientsDesignedRandomizationusedtocomparevarioussw