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AdditionalResources:1.MannJJ.TheMedicalManagementofDepression.NewEnglandJournalofMedicine2005;353:1819-342.GelenbergAJ,HopkinsHS.AssessingandTreatingDepressioninPrimaryCareMedicine.AmericanJournalofMedicine.2007;120:105-1083.TheTexasImplementationofMedicationAlgorithms:UpdatetotheAlgorithmsforTreatmentofBipolarIDisorder.SuppesT.,etal.JournalofClinicalPsychiatry2005;66:870-886NeurotransmitterNeurotransmitterPathwayFunctionRemovalMechanismDiseaseMedicationDopamine(多巴胺)inhibitorytransporterMAOCOMTparkinsonschizophreniadopamineagonistSerotonin(5-HT)(5羥色胺)excititorytransporterMAO抑郁anxietyschizophreniaSSRIs(選擇性5HT再吸收抑制劑)SNRIs(5-HT和NE雙重再攝取抑制劑)atypicalNoradrenergic(去甲腎上腺素)excititorytransporterMAOCOMT抑郁bipolaranxietyTCAs(三環(huán)類抗抑郁)GABA(r-氨基丁酸)inhibitorytransporterseizure疼痛anxietyparkinsongabapentin(加巴噴丁)GlutamateexcititorytransporteralzheimerpainparkinsonmemantinesynthesizingpackagingreleasingbindingremovalEpidemiologyoccursin1in8individualsduringtheirlifetime2-3%ofmales;5-9%offemalescomorbidities:anxietyimpulsecontroldisordersubstanceabuseAverageOnset:mid-20s,butcanmanifestatanyageEpidemiologytriggeringfactors:deathoflovedone,divorce,chronicmedicalconditionsendocrinedisorder:Cushing’sdz,Addison’sdz,....Implication:>50%ofcompletedsuicidesinvolvedepressionannualcost:$44billionEpidemiologyCourseofillnesssingleepisoderecurrentepisodes60%ofPtsw/singleepisode:developa2ndepisodePtsw/2ndepisode:70%chanceofhavinga3rdepisodePtsw/3rdepisode:90%chanceofhavinga4thepisodeEpidemiology5-10%ofPtsw/singledepressiveepisode:willeventuallyexperiencemanicepisodePsw/residualsymptomsmorelikelytosufferfromfuturedepressiveepisodesPathophysiologyexactetiologyunknownmostlikelymultifactorial:genetic,environmental,biological1stdegreerelativew/depression1.5-3timesmorelikelytodevelopbrainimaginghasidentifiednumerousregionsofalteredstructureactivityPathophysiologyPositronEmissionTomography(PET)studies↓in5-HTtransportersalteredpost-synaptic5-HT-receptorbindingPtssufferingw/depressionbrain5-HTandNElevels:DONOTdifferfromcontrols↑5-HTandNEtransmission:DOEStreatsymptoms.Diagnosisdepressedmoodlackofinterest/pleasurealmostdaily≥2weeks.alsomusthave≥4additionalsymptoms(SIGECAPS)Sleep↑↓Concentration↓Interest↓Appetite↑↓GuiltPsychomotorEnergy↓SuicideDiagnosisSIGECAPS:mustbeaccompaniedbysignificantimpairmentinfunctioning.cannotbeduetoeffectsofsubstanceabuse,drugsideeffect,toxinexposurebereavement(within2monthsofloss).ClassificationofAntidepressants(ADs)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)fluvoxamine5-HT和NE雙重再攝取抑制劑(SNRIs)萬(wàn)拉法新(venlafaxine)杜洛西汀(duloxetine)第二代(2ndGeneration)安菲他酮(bupropion)米氮平(mirtazapine)nefazodone三環(huán)類(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)imipraminedesipramineclomipramine單胺氧化酶抑制劑(MAOIs)phenelzinetranylcypromine司來(lái)吉蘭(selegiline)GeneralTreatmentPrinciplesDurationofUse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(duì)復(fù)發(fā)/慢性抑郁候選患者：≥3episodesofmajordepression≥2episodes+≥1ofthefollowing:*情緒障礙家族史，快速?gòu)?fù)發(fā)，年老/嚴(yán)重發(fā)作維持治療=同樣藥物/同樣劑量Response(起效)≥50%↓insymptomsRemission(緩解)

completeresolutionofsymptomsRelapse(復(fù)發(fā))returnofsymptomsafteraperiodofremissionResponseResponse:≥50%↓insymptoms50%ofPtswillstillhaveresidualsymptomsPredictorsofresponseabsenceofneurovegetativesymptomspastresponsefamilialresponsepatientsadherencewithvisitsandmeds6-12weeks4-9months≥1yearResponsevs.RemissionDiscontinuation/Withdrawalsyndrome戒斷癥狀vividdreams,惡夢(mèng),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)SuicidalityBlackBoxWarning:↑<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(wú)治療>治療IntroductionofFluoxtineandotherADsinlate1980sSerotoninSyndrome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...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)anbelifethreateningVideoAntidepressants(ADs)三環(huán)類(TCAs)選擇性5-HT再攝取抑制劑(SSRI)5-HT和NE雙重再攝取抑制劑(SNRI)第二代ADs單胺氧化酶抑制劑(MAOI)TricyclicAntidepressants三環(huán)類(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)丙咪嗪(imipramine)desipramineclomipramineTCAs1線用藥：1960s-1980s不同程度上阻斷NE和5HT重吸收NE5HTImipramine+++++阿米替林(amitriptyline)++++Clomipramine+++++Desipramine++++0TCAs“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,serumlevelsplayalargeroleindeterminingdoseDisadvantages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(jué)、煩躁不安)Desipramine&去甲替林(nortriptyline):lessanticholinergic通常不用于老年患者Disadvantages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(guò)量劑量可致命Advantages廉價(jià)longtrackrecordplasmalevelsareusefulinmonitoring也可用于治療疼痛、焦慮、失眠，預(yù)防偏頭痛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)fluvoxamineMOA抑制5-HT在突出的重吸收對(duì)組胺、膽堿、或腎上腺素受體無(wú)吸引力5-HT1A=antidepressantaction5-HT2&5-HT3=胃腸和性功能副作用TreatmentofChoiceAdvantagesoverTCAs過(guò)量劑量不會(huì)致命鎮(zhèn)靜作用更少體重增加更少無(wú)心血管副作用心臟傳導(dǎo)改變直立性低血壓尿潴留TreatmentofChoiceeffectiveforseveralcomorbiditesaswell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(wú)關(guān)給藥:每日一次5-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-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(yáng)痿，特別是sertralineInteractionsMAOI2星期清空期(washoutperiod),Fluoxetine需5星期fluoxetine→MAOIs:5weeksMAOIS→fluoxetine：2weeksInteractions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,phenytoinconcentrationsDosing開(kāi)始低劑量逐漸↑劑量：↑頻率小于每周(nosoonerthanweekly)4-6周后評(píng)價(jià)效果somesymptomsmayrespondin1-2weeksaimforremissionofsymptomsand/ortargetdoseSSRIs初始劑量mgqd最大劑量mgqdT1/2hourCYPNotes氟西汀(fluoxetine)1080*metabolite84148potentinhibitorof2D6and3A4moststimulating最容易厭食帕羅西汀(Paroxetine)105021potentinhibitorof2D625mgCR=20mgIRCRformisNOTlongeracting:designedto↓GIupset最多抗膽堿副作用舍曲林(Sertraline)5020026moderateinhibitorof2D6(higherdoses)最多腹瀉最多男性性功能障礙西酞普蘭(Citalopram)206035moderateinhibitorof2D6(higherdoses)艾司西酞普蘭(Escitalopram)102035moderateinhibitorof2D6(higherdoses)S-enantiomerofcitalopram氟伏沙明(Fluvoxamine)5030015potentinhibitorof1A2,2C19,3A最多惡心副作用最多便秘副作用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(wú)效果必須與奧氮平(olanzapine)合用定期重新評(píng)估治療的必要性fluoxetine初始劑量:20mgqpm逐漸降低劑量停藥Serotonin&NorepinephrineReuptakeInhibitors5-HT和NE雙重再攝取抑制劑(SNRIs)萬(wàn)拉法新(venlafaxine)Des-venlafaxine杜洛西汀(duloxetine)MOAofSNRIs“dual-acting”ADs:NE&5-HT→maybeeffectiveinPtswho’vefailedSSRIsbutlittleevidencetosupportadifferenceVenlafaxinedose<200mgqd=5-HTreuptakeprimarily>200mgqd=5-HT&NEreuptakeXRformulationpreferredAdvantage幾乎無(wú)直立性低血壓副作用P450酶的弱抑制劑VenlafaxineDisadvantage: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DesvanlafaxineFDAapprovalFebruary2008activemetaboliteofVenlafaxineDuloxetine5-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.venlafaxine2ndGenerationADs第2代抗抑郁安菲他酮(bupropion)米氮平(mirtazapine)nefazodoneBupropion抑制NE和DA的重吸收multipledoseformulations:IR,SR,XLIR=upto150mgperdose:100mgtidSR=upto200mgperdose:100mgbidXL=upto450mgperdose:300mgqamBupropionAdvantagesnotassociatedwithrapidcycling性功能障礙概率低體重↑很少無(wú)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Mirtazapine↑serotonergictransmission阻斷5-HT2A,5-HT2C,&5-HT3受體potentH1antagonistMirtazapineAdvantagesT1/2=20-40hours,QD藥物相互作用最少無(wú)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”Nefazodoneblocks5-HT2receptorinhibits5-HTreuptakerarelyusedduetoblack-boxwarninglife-threateninghepaticfailureMonoamineOxidaseInhibitors單胺氧化酶抑制劑(MAOIs)phenelzinetranylcypromine司來(lái)吉蘭(selegiline)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dietSelegiline司來(lái)吉蘭(selegiline)PO:MAO-Bselective(primarily↑DA)透皮(transdermal)bypasses1stpassmetabolismallowshigherCNSconcentrationsbypassesintestinalinhibitionofMAO-A*noneedfortyramine-freediet@6mgqd(initial)doseAugmentationOptionsinTreatmentofDepressionLithium(鋰):treatbipolar,mania,schizoaffectived/oThyroidhomone(甲狀腺激素)Buspirone(丁螺環(huán)酮):treatanxietyAtypicalAntipsychotics:aripiprazole(阿立哌唑)PsychostimulantDrugs:dextroamphetamine/amphetamineNonpharmacologicTreatmentofDepressionECT(electrocompulsivetreatment)mosteffectTxforMDD(95%)PhototherapyespeciallyforseasonalaffectivedisorderrTMS(repetitiveTranscranialMagneticStimulation)ChoiceofAntidepressant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(wú)效≠該類藥物中其他藥物無(wú)效!ChoiceamongAgentsbasedon...1.SideeffectDrug失眠&激動(dòng)鎮(zhèn)靜直立性低血壓抗膽堿惡心性功能障礙體重↑SSRIs++0/+0/+0/++++++文拉法辛(Venlafaxine)++0/+0/+0/+++++0/+杜洛西汀(Duloxetine)0/++0/++++0/+0/+米氮平(Mirtazapine)0/+++++0/+0/+0/++++安菲他酮(Bupropion)++0/+0/+++0/+0/+2.PotentialforInteractionDrug1A22C92C192D63A3/4氟西汀(Fluoxetine)++++/+++++++舍曲林(Setraline)++++/++++帕羅西汀(Paroxetine)+++++++氟伏沙明(Fluvoxamine)+++++++++++安菲他酮(Bupropion)000+0文拉法辛(Venlafaxine)00000米氮平(Mirtazapine)000+0杜洛西汀(Duloxetine)000++03.安全性?年齡，過(guò)量用藥風(fēng)險(xiǎn)，懷孕等f(wàn)luoxetine:mostdata,still“C”paroxetine,“D”4.患者傾向5.患者對(duì)過(guò)去治療的反應(yīng)6.費(fèi)用SequencedTreatmentAlternativestoResolveDepression7yeartrialfundedbyNIMH,4041patientsDesignedRandomizationusedtocomparevariousswitchingoraugmentingstrategieseithercommonlyusedorthatarebasedonpharmacologicreasoning(12weeksperlevel)*STAR*DTrialLEVEL1INITIALTREATMENT: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:TranylcypromineorMirtazapinecombinedwithVenlafaxineERAtlevel1?~30%remission;47%responsewithcitalopramInPtsfailtoobtainadequatebenefitfrom≥2treatmenttrialsonlymodestresponsescanbeexpectedfromeachsubsequenttreatmenttrial.AfterseveralpreviousantidepressanttrialsT3moretolerableandeasiertousethanlithiumAftermultiplefailedtrials,Venlafaxine+Mirtazapineispreferredover