Depression王天晟,Pharm.D.,R.Ph.北京大學藥學院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北醫藥物治療學抗抑郁藥課件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:北醫藥物治療學抗抑郁藥課件GeneralTreatmentPrinciplesGeneralTreatmentPrinciplesDurationofUse所有ADs需要≥4周治療(最好8周)@足夠劑量治療劑量持續6-9個月,更多建議為12個月維持治療≥2年:針對復發/慢性抑郁候選患者：≥3episodesofmajordepression≥2episodes+≥1ofthefollowing:*情緒障礙家族史，快速復發，年老/嚴重發作維持治療=同樣藥物/同樣劑量DurationofUse所有ADs需要≥4周治療(最北醫藥物治療學抗抑郁藥課件ResponseResponse:≥50%↓insymptoms50%ofPtswillstillhaveresidualsymptomsPredictorsofresponseabsenceofneurovegetativesymptomspastresponsefamilialresponsepatientsadherencewithvisitsandmedsResponseResponse:≥50%↓insym6-12weeks4-9months≥1yearResponsevs.Remission6-12weeks4-9months≥1yearResDiscontinuation/Withdrawalsyndrome戒斷癥狀vividdreams,惡夢,顫動,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歲患者自殺風險@治療的第一個月自殺風險：無治療>治療IntroductionofFluoxtineandotherADsinlate1980sBlackBoxWarning:↑<25歲患者自殺風險SerotoninSyndrome惶惑煩躁不安肌陣攣反射亢進出汗顫動顫抖痢疾輕度狂躁不協調性...SerotoninSyndrome惶惑SerotoninSyndrome5-HT綜合征(5-HTstorm)可以↑5-HT水平的藥物都有此風險veryrare,<1%,especiallywithmonotherapy兩種↑5-HT藥物合用時風險↑canbelifethreateningSerotoninSyndrome5-HT綜合征(5-HVideoVideoAntidepressants(ADs)Antidepressants(ADs)TricyclicAntidepressants三環類(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)丙咪嗪(imipramine)desipramineclomipramineTricyclicAntidepressants三環類(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(激動、錯覺、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延時5-HT副作用增加癲癇發作的可能性轉換為狂躁:≤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longtrackrecordplasmalevelsareusefulinmonitoring也可用于治療疼痛、焦慮、失眠，預防偏頭痛Advantages廉價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過量劑量不會致命鎮靜作用更少體重增加更少無心血管副作用心臟傳導改變直立性低血壓尿潴留TreatmentofChoiceAdvantagesTreatmentofChoiceeffectiveforseveralcomorbiditesaswell廣泛性焦慮癥社交恐懼癥強迫癥貪食,經前期煩躁不安的紊亂血漿濃度和臨床效果無關給藥:每日一次TreatmentofChoiceeffectivef5-HTSideeffectsEarlyonset惡心:特別是舍曲林(sertraline),1-2星期產生耐受性焦慮&激動: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↑carbamazepine,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周后評價效果somesymptomsmayrespondin1-2weeksaimforremissionofsymptomsand/ortargetdoseDosing開始低劑量北醫藥物治療學抗抑郁藥課件Fluoxetinetreatresistant,急性治療現階段抑郁已用2個不同抗抑郁藥治療，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:監控血壓戒斷癥狀顯著VenlafaxineDisadvantage:DesvanlafaxineFDAapprovalFebruary2008activemetaboliteofVenlafaxineDesvanlafaxineFDAapprovalFebDuloxetine5-HT&NEreuptakeinhibitorthroughentiredoserange可治療神經痛和其他慢性疼痛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：失眠,焦慮顫動↑癲癇可能性禁用于癲癇,飲食失調,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↑鎮靜riskof↑cholesterol“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/復發性抑郁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(丁螺環酮):treatanxietyAtypicalAntipsychotics:aripiprazole(阿立哌唑)PsychostimulantDrugs:dextroamphetamine/amphetamineLithium(鋰):treatbipolar,manNonpharmacologicTreatmentofDepressionNonpharmacologicTreatmentofECT(electrocompulsivetreatment)mosteffectTxforMDD(95%)PhototherapyespeciallyforseasonalaffectivedisorderrTMS(repetitiveTranscranialMagneticStimulation)ECT(electrocompulsivetreatmeChoiceofAntidepressantChoiceofAntidepressant非復雜的單相抑郁:所有抗抑郁藥視為等效exceptions:(levelofevidenceisnotgreat)TCAsclearlyefficaciousinseveredepressionbupropionmaytheoreticallyworkwellinPtsw/apathyvenlafaxinemaybemoreeffectiveinTx-resistantdepressionthanSSRIsMAOIsparticularlyeffectiveforPtswithatypicalfeatures(SSRIsalsoshowpromise)某類藥物中某個藥物無效≠該類藥物中其他藥物無效!非復雜的單相抑郁:所有抗抑郁藥視為等效ChoiceamongAgentsbasedon...ChoiceamongAgentsbasedon..1.Sideeffect1.Sideeffect2.PotentialforInteraction2.PotentialforInteraction3.安全性?年齡，過量用藥風險，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6.費用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個月，性生活質量下降，食欲和體重增加，嗜睡嚴重，有自殺傾向。實習醫生建議用阿米替林(amitriptyline)，藥師的用藥方案？C12:SW,27歲男性，失業已有半年，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”，希望醫生換藥，藥師建議的用藥方案？C13:GW,36歲男性，大學教師，接受氟西汀(fluoxetine)40mgqam治療抑郁9個月，效果不加，醫生決定換藥，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個月中情緒嚴重低落，由于長時間加班導致很大的工作壓力。KB想多花時間和家人在一起，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個星期后回到藥房取藥，告訴藥師LB自己感覺心情不錯，睡眠也像過去一樣不錯。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。此時藥師向醫生建議的用藥方案？C11:AG,36歲女性,抑郁已有2個月，性生活質量下C16:AK,48歲男性，因中度抑郁住院，這是他去年以來的第3次抑郁發作。正服用舍曲林(sertraline)150mgqd.他妻子說AK經常連續3，4天沒有服藥，由于需要因為工作旅行時忘記了攜帶藥品。AK成人這種時候自己會變得非常憂慮，而且經常覺得惡心。為解決AK依從性差的問題，藥師向醫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，經常惡心，甲狀腺功能減退癥，最近由于飲食失調住院。醫生的處方是: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，要求醫生換藥。藥師給醫生建議的用藥方案為？C19：AO,60歲男性，抑郁癥同時有慢性疼痛。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，互聯網公司CEO,年初開始失眠，服用安定已有5個月。因公司業績問題，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.北京大學藥學院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北醫藥物治療學抗抑郁藥課件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:北醫藥物治療學抗抑郁藥課件GeneralTreatmentPrinciplesGeneralTreatmentPrinciplesDurationofUse所有ADs需要≥4周治療(最好8周)@足夠劑量治療劑量持續6-9個月,更多建議為12個月維持治療≥2年:針對復發/慢性抑郁候選患者：≥3episodesofmajordepression≥2episodes+≥1ofthefollowing:*情緒障礙家族史，快速復發，年老/嚴重發作維持治療=同樣藥物/同樣劑量DurationofUse所有ADs需要≥4周治療(最北醫藥物治療學抗抑郁藥課件ResponseResponse:≥50%↓insymptoms50%ofPtswillstillhaveresidualsymptomsPredictorsofresponseabsenceofneurovegetativesymptomspastresponsefamilialresponsepatientsadherencewithvisitsandmedsResponseResponse:≥50%↓insym6-12weeks4-9months≥1yearResponsevs.Remission6-12weeks4-9months≥1yearResDiscontinuation/Withdrawalsyndrome戒斷癥狀vividdreams,惡夢,顫動,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歲患者自殺風險@治療的第一個月自殺風險：無治療>治療IntroductionofFluoxtineandotherADsinlate1980sBlackBoxWarning:↑<25歲患者自殺風險SerotoninSyndrome惶惑煩躁不安肌陣攣反射亢進出汗顫動顫抖痢疾輕度狂躁不協調性...SerotoninSyndrome惶惑SerotoninSyndrome5-HT綜合征(5-HTstorm)可以↑5-HT水平的藥物都有此風險veryrare,<1%,especiallywithmonotherapy兩種↑5-HT藥物合用時風險↑canbelifethreateningSerotoninSyndrome5-HT綜合征(5-HVideoVideoAntidepressants(ADs)Antidepressants(ADs)TricyclicAntidepressants三環類(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)丙咪嗪(imipramine)desipramineclomipramineTricyclicAntidepressants三環類(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(激動、錯覺、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延時5-HT副作用增加癲癇發作的可能性轉換為狂躁:≤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longtrackrecordplasmalevelsareusefulinmonitoring也可用于治療疼痛、焦慮、失眠，預防偏頭痛Advantages廉價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過量劑量不會致命鎮靜作用更少體重增加更少無心血管副作用心臟傳導改變直立性低血壓尿潴留TreatmentofChoiceAdvantagesTreatmentofChoiceeffectiveforseveralcomorbiditesaswell廣泛性焦慮癥社交恐懼癥強迫癥貪食,經前期煩躁不安的紊亂血漿濃度和臨床效果無關給藥:每日一次TreatmentofChoiceeffectivef5-HTSideeffectsEarlyonset惡心:特別是舍曲林(sertraline),1-2星期產生耐受性焦慮&激動: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↑carbamazepine,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周后評價效果somesymptomsmayrespondin1-2weeksaimforremissionofsymptomsand/ortargetdoseDosing開始低劑量北醫藥物治療學抗抑郁藥課件Fluoxetinetreatresistant,急性治療現階段抑郁已用2個不同抗抑郁藥治療，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:監控血壓戒斷癥狀顯著VenlafaxineDisadvantage:DesvanlafaxineFDAapprovalFebruary2008activemetaboliteofVenlafaxineDesvanlafaxineFDAapprovalFebDuloxetine5-HT&NEreuptakeinhibitorthroughentiredoserange可治療神經痛和其他慢性疼痛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：失眠,焦慮顫動↑癲癇可能性禁用于癲癇,飲食失調,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↑鎮靜riskof↑cholesterol“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/復發性抑郁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(丁螺環酮):treatanxietyAtypicalAntipsychotics:aripiprazole(阿立哌唑)PsychostimulantDrugs:dextroamphetamine/amphetamineLithium(鋰):treatbipolar,manNonpharmacologicTreatmentofDepressionNonpharmacologicTreatmentofECT(electrocompulsivetreatment)mosteffectTxforMDD(95%)PhototherapyespeciallyforseasonalaffectivedisorderrTMS(repetitiveTranscranialMagneticStimulation)ECT(electrocompulsivetreatmeChoiceofAntidepressantChoiceofAntidepressant非復雜的單相抑郁:所有抗抑郁藥視為等效exceptions:(levelofevidenceisnotgreat)TCAsclearlyefficaciousinseveredepressionbupropionmaytheoreticallyworkwellinPtsw/apathyvenlafaxinemaybemoreeffectiveinTx-resistantdepressionthanSSRIsMAOIsparticularlyeffectiveforPtswithatypicalfeatures(SSRIsalsoshowpromise)某類藥物中某個藥物無效≠該類藥物中其他藥物無效!非復雜的單相抑郁:所有抗抑郁藥視為等效ChoiceamongAgentsbasedon...ChoiceamongAgentsbasedon..1.Sideeffect1.Sideeffect2.PotentialforInteraction2.PotentialforInteraction3.安全性?年齡，過量用藥風險，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6.費用3.安全性?SequencedTreatmentAlternativestoResolveDepression7yeartrialfundedbyNIMH,4041patientsDesignedRandomizationusedtocomparevarioussw