北医药物治疗学抗抑郁药课件.ppt

1、Depression王天晟,Pharm.D.,R.Ph.北京大学药学院Additional Resources:1.Mann JJ.The Medical Management of Depression.New England Journal of Medicine 2005;353:1819-34 2.Gelenberg AJ,Hopkins HS.Assessing and Treating Depression in Primary Care Medicine.American Journal of Medicine.2007;120:105-1083.The Texas Implem

2、entation of Medication Algorithms:Update to the Algorithms for Treatment of Bipolar I Disorder.Suppes T.,et al.Journal of Clinical Psychiatry 2005;66:870-886NeurotransmitterNeurotransmitter PathwayFunctionRemoval MechanismDisease MedicationDopamine(多巴胺)inhibitorytransporterMAOCOMTparkinsonschizophre

3、niadopamine agonistSerotonin(5-HT)(5羟色胺)excititorytransporterMAO抑郁anxietyschizophreniaSSRIs(选择性5HT再吸收抑制剂)SNRIs(5-HT和NE双重再摄取抑制剂)atypicalNoradrenergic(去甲肾上腺素)excititorytransporterMAOCOMT抑郁bipolaranxietyTCAs(三环类抗抑郁)GABA(r-氨基丁酸)inhibitorytransporterseizure疼痛anxietyparkinsongabapentin(加巴喷丁)Glutamateexcit

4、itorytransporteralzheimerpainparkinsonmemantinesynthesizing packaging releasingbindingremovalEpidemiologyoccurs in 1 in 8 individuals during their lifetime2-3%of males;5-9%of femalescomorbidities:anxietyimpulse control disordersubstance abuseAverage Onset:mid-20s,but can manifest at any ageEpidemiol

5、ogytriggering factors:death of loved one,divorce,chronic medical conditionsendocrine disorder:Cushings dz,Addisons dz,.Implication:50%of completed suicides involve depressionannual cost:$44 billionEpidemiologyCourse of illnesssingle episoderecurrent episodes 60%of Pts w/single episode:develop a 2nd

6、episodePts w/2nd episode:70%chance of having a 3rd episodePts w/3rd episode:90%chance of having a 4th episodeEpidemiology5-10%of Pts w/single depressive episode:will eventually experience manic episodePs w/residual symptomsmore likely to suffer from future depressive episodesPathophysiologyexact eti

7、ology unknownmost likely multifactorial:genetic,environmental,biological1st degree relative w/depression1.5-3 times more likely to developbrain imaging has identified numerous regions of alteredstructureactivityPathophysiologyPositron Emission Tomography(PET)studies in 5-HT transportersaltered post-

8、synaptic 5-HT-receptor bindingPts suffering w/depression brain 5-HT and NE levels:DO NOT differ from controls5-HT and NE transmission:DOES treat symptoms.Diagnosisdepressed moodlack of interest/pleasure almost daily 2 weeks.also must have 4 additional symptoms(SIGECAPS)Sleep Concentration Interest A

9、ppetite GuiltPsychomotorEnergySuicideDiagnosisSIGECAPS:must be accompanied by significant impairment in functioning.cannot be due to effects of substance abuse,drug side effect,toxin exposurebereavement(within 2 months of loss).Classification of Antidepressants(ADs)选择性5-HT再摄取抑制剂(SSRIs)氟西汀(fluoxetine

10、)帕罗西汀(paroxetine)舍曲林(sertraline)西酞普兰(citalopram)艾司西酞普兰(escitalopram)fluvoxamine5-HT和NE双重再摄取抑制剂(SNRIs)万拉法新(venlafaxine)杜洛西汀(duloxetine)第二代(2nd Generation)安菲他酮(bupropion)米氮平(mirtazapine)nefazodone三环类(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)imipraminedesipramineclomipramine单胺氧化酶抑制剂(MAOIs)phenelzinet

11、ranylcypromine司来吉兰(selegiline)General Treatment PrinciplesDuration of Use所有ADs需要 4周治疗(最好8周)足够剂量治疗剂量持续6-9个月,更多建议为12个月维持治疗2年:针对复发/慢性抑郁候选患者：3 episodes of major depression2 episodes+1 of the following:*情绪障碍家族史，快速复发，年老/严重发作维持治疗=同样药物/同样剂量Response(起效)50%in symptomsRemission(缓解)complete resolution of sympto

12、msRelapse(复发)return of symptoms after a period of remissionResponseResponse:50%in symptoms50%of Pts will still have residual symptoms Predictors of responseabsence of neurovegetative symptomspast responsefamilial responsepatients adherence with visits and meds6-12 weeks4-9 months1 yearResponse vs.Re

13、missionDiscontinuation/Withdrawal syndrome戒断症状vivid dreams,恶梦,颤动,头晕,头痛,电休克感,恶心不建议立即停药,(逐渐减小剂量7-10天）例外：氟西汀(Fluoxetine)SuicidalityBlack Box Warning:治疗Introduction of Fluoxtine and other ADs in late 1980sSerotonin Syndrome惶惑烦躁不安肌阵挛反射亢进出汗颤动颤抖痢疾轻度狂躁不协调性.Serotonin Syndrome5-HT综合征(5-HT storm)可以 5-HT 水平的药物都

14、有此风险very rare,1%,especially with monotherapy两种5-HT药物合用时风险 can be life threateningVideoAntidepressants(ADs)三环类(TCAs)选择性5-HT再摄取抑制剂(SSRI)5-HT和NE双重再摄取抑制剂(SNRI)第二代ADs 单胺氧化酶抑制剂(MAOI)Tricyclic Antidepressants三环类(TCAs)阿米替林(amitriptyline)去甲替林(nortriptyline)丙咪嗪(imipramine)desipramineclomipramineTCAs1线用药：1960s

15、-1980s不同程度上阻断NE和5HT重吸收NE5HTImipramine+阿米替林(amitriptyline)+Clomipramine+Desipramine+0TCAs“dirty receptor binding”:同时阻断其他受体组胺胆碱alpha肾上腺素肝代谢剂量：large interpatient pharmacokinetic variability,serum levels play a large role in determining doseDisadvantages抗胆碱(anticholinergic)副作用口干燥视力模糊尿潴留便秘中枢神经(激动、错觉、烦躁不安

16、)Desipramine&去甲替林(nortriptyline):less anticholinergic通常不用于老年患者Disadvantages心血管副作用:最好避免用于潜在心血管疾病患者直立性低血压心跳加速传导延时5-HT副作用增加癫痫发作的可能性转换为狂躁:10%of patients can switch rapidly过量剂量可致命Advantages廉价long track recordplasma levels are useful in monitoring也可用于治疗疼痛、焦虑、失眠，预防偏头痛Selective Serotonin Reuptake Inhibitors

17、选择性5-HT再摄取抑制剂(SSRIs)氟西汀(fluoxetine)帕罗西汀(paroxetine)舍曲林(sertraline)西酞普兰(citalopram)艾司西酞普兰(escitalopram)fluvoxamineMOA抑制5-HT在突出的重吸收对组胺、胆碱、或肾上腺素受体无吸引力5-HT1A=antidepressant action5-HT2&5-HT3=胃肠和性功能副作用Treatment of ChoiceAdvantages over TCAs过量剂量不会致命镇静作用更少体重增加更少无心血管副作用心脏传导改变直立性低血压尿潴留Treatment of Choiceeffe

18、ctive for several comorbidites as well 广泛性焦虑症社交恐惧症 强迫症贪食,经前期烦躁不安的紊乱血浆浓度和临床效果无关给药:每日一次5-HT Side effectsEarly onset恶心:特别是舍曲林(sertraline),1-2星期产生耐受性焦虑&激动:初始明显，然后减弱，氟西汀(fluoxetine)&sertraline最明显：5-HT Side effectsLate onset失眠:初始可能镇静，特别是帕罗西汀(paroxetine)体重改变:初始可能体重，后期,特别是paroxetine性功能障碍:性欲，性快感，阳痿，特别是sertra

19、lineInteractionsMAOI2星期清空期(wash out period),Fluoxetine需5星期fluoxetineMAOIs:5weeksMAOISfluoxetine：2weeksInteractions其他可能5-HT水平的药物曲马多(tramadol),哌替啶(meperidine),triptan,e.g.舒马普坦(sumatriptan),rizatriptan.TCAs,SNRIothers due to cytochrome P450 effects:e.g.fluoxetinemaycarbamazepine,alprazolam,phenytoin co

20、ncentrationsDosing开始低剂量逐渐剂量：频率小于每周(no sooner than weekly)4-6 周后评价效果some symptoms may respond in 1-2weeksaim for remission of symptoms and/or target doseSSRIs初始剂量mg qd最大剂量mg qdT1/2hourCYPNotes氟西汀(fluoxetine)1080*metabolite 84148potent inhibitor of 2D6 and 3A4most stimulating最容易厌食帕罗西汀(Paroxetine)10502

21、1potent inhibitor of 2D625mg CR=20mg IRCR form is NOT longer acting:designed to GI upset最多抗胆碱副作用舍曲林(Sertraline)5020026moderate inhibitor of 2D6(higher doses)最多腹泻最多男性性功能障碍西酞普兰(Citalopram)206035moderate inhibitor of 2D6(higher doses)艾司西酞普兰(Escitalopram)102035moderate inhibitor of 2D6(higher doses)S-en

22、antiomer of citalopram氟伏沙明(Fluvoxamine)5030015potent inhibitor of 1A2,2C19,3A最多恶心副作用最多便秘副作用Fluoxetinetreat resistant,急性治疗现阶段抑郁已用2个不同抗抑郁药治疗，足够剂量,疗程仍无效果必须与奥氮平(olanzapine)合用定期重新评估治疗的必要性fluoxetine 初始剂量:20mg qpm逐渐降低剂量停药Serotonin&Norepinephrine Reuptake Inhibitors5-HT和NE双重再摄取抑制剂(SNRIs)万拉法新(venlafaxine)Des

23、-venlafaxine杜洛西汀(duloxetine)MOA of SNRIs“dual-acting”ADs:NE&5-HTmay be effective in Pts whove failed SSRIsbut little evidence to support a differenceVenlafaxinedose200mg qd=5-HT&NE reuptakeXR formulation preferredAdvantage几乎无直立性低血压副作用P450酶的弱抑制剂VenlafaxineDisadvantage:common“5-HT side effect”1.恶心2.嗜睡

24、，失眠3.厌食4.性功能障碍可能舒张压:监控血压戒断症状显著DesvanlafaxineFDA approval February 2008active metabolite of VenlafaxineDuloxetine5-HT&NE reuptake inhibitor through entire dose range可治疗神经痛和其他慢性疼痛long term studies indicate low potential for weight may have less sexual dysfunction than SSRIs副作用common 5-HT side effects直

25、立性低血压lower risk of BP vs.venlafaxine2nd Generation ADs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multiple dose formulations:IR,SR,XLIR=up to 150 mg per dose:100mg tidSR=up to 200mg per dose:100mg bidXL=up to 450mg per dose:300mg qam BupropionAdvantagesnot associated with rapi

26、d cycling性功能障碍概率低体重很少无抗胆碱副作用可用于戒烟治疗Disadvantagesside effects激活效应：失眠,焦虑颤动癫痫可能性禁用于癫痫,饮食失调,酒精戒断Mirtazapine serotonergic transmission阻断5-HT2A,5-HT2C,&5-HT3受体potent H1 antagonistMirtazapineAdvantagesT1/2=20-40 hours,QD药物相互作用最少无性功能障碍副作用胃肠道副作用SSRIssedation may be helpfulDisadvantages体重镇静risk of cholesterol

27、“zapine”Nefazodoneblocks 5-HT2 receptorinhibits 5-HT reuptakerarely used due to black-box warninglife-threatening hepatic failureMonoamine Oxidase Inhibitors单胺氧化酶抑制剂(MAOIs)phenelzinetranylcypromine司来吉兰(selegiline)MAOIs抑制单胺氧化酶breakdown of NE,5-HT,&DA is inhibitedbreakdown of tyramine(酪胺)is inhibitedm

28、onoamine compound derived from amino acid tyrosineeffects of drugs last 14 days with irreversible inhibitorsUse=非典型/复发性抑郁Side Effects直立性低血压体重失眠、不安性功能障碍高血压危象：with tyramine containing foods,pressors枕骨头痛，颈部僵直BP,心悸恶心/呕吐，出汗Interactions=numerous哌替啶(meperidine):高烧，高血压，昏迷Sympathomimetics:especially indirect

29、Rx:安非他明(amphetamine),右旋安非他明(dextroamphetamine),哌甲酯(methylphenidate)OTC decongestant:伪麻黄碱(pseudoephedrine),去氧肾上腺素(phenylephrine)SSRIs&其他抗抑郁药:5-HT综合征dietSelegiline司来吉兰(selegiline)PO:MAO-B selective(primarily DA)透皮(transdermal)bypasses 1st pass metabolismallows higher CNS concentrationsbypasses intesti

30、nal inhibition of MAO-A*no need for tyramine-free diet 6mg qd(initial)dose Augmentation Options in Treatment of DepressionLithium(锂):treat bipolar,mania,schizoaffective d/oThyroid homone(甲状腺激素)Buspirone(丁螺环酮):treat anxietyAtypical Antipsychotics:aripiprazole(阿立哌唑)Psychostimulant Drugs:dextroamphetam

31、ine/amphetamineNonpharmacologic Treatment of Depression ECT(electrocompulsive treatment)most effect Tx for MDD(95%)Phototherapyespecially for seasonal affective disorderrTMS(repetitive Transcranial Magnetic Stimulation)Choice of Antidepressant非复杂的单相抑郁:所有抗抑郁药视为等效exceptions:(level of evidence is not g

32、reat)TCAs clearly efficacious in severe depressionbupropion may theoretically work well in Pts w/apathyvenlafaxine may be more effective in Tx-resistant depression than SSRIsMAOIs particularly effective for Pts with atypical features(SSRIs also show promise)某类药物中某个药物无效该类药物中其他药物无效!Choice among Agents

33、 based on.1.Side effectDrug失眠&激动镇静直立性低血压抗胆碱 恶心性功能障碍体重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.Potential for InteractionDrug1A22C92C192D63A3/4氟西汀(Fluoxetine)+/+舍曲林(Setraline)+/+帕罗西汀(Paroxetine)+氟伏沙明(Fluvoxamine)

34、+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.安全性年龄，过量用药风险，怀孕等fluoxetine:most data,still“C”paroxetine,“D”4.患者倾向5.患者对过去治疗的反应6.费用Sequenced Treatment Alternatives to Resolve Depression7 year trial funded by NIMH,4041 patientsDesignedRandomization used to compare

35、 various switching or augmenting strategies either commonly used or that are based on pharmacologic reasoning(12 weeks per level)*STAR*D TrialAt level130%remission;47%response with citalopramIn Pts fail to obtain adequate benefit from 2 treatment trialsonly modest responses can be expected from each

36、 subsequent treatment trial.After several previous antidepressant trialsT3 more tolerable and easier to use than lithiumAfter multiple failed trials,Venlafaxine+Mirtazapine is preferred over Tranylcypromine ConclusionC11:AG,36岁女性,抑郁已有2个月，性生活质量下降，食欲和体重增加，嗜睡严重，有自杀倾向。实习医生建议用阿米替林(amitriptyline)，药师的用药方案？

37、C12:SW,27岁男性，失业已有半年，吸烟，接受抑郁治疗，西酞普兰(citalopram)20mg/d 已有2星期，患者抱怨“药物不起作用”，希望医生换药，药师建议的用药方案？C13:GW,36岁男性，大学教师，接受氟西汀(fluoxetine)40mg qam治疗抑郁9个月，效果不加，医生决定换药，使用司来吉兰(selegiline),药师建议用药方案？C14:KB,36岁女性，由于自杀倾向和大量吞服药物入院。KB过去2个月中情绪严重低落，由于长时间加班导致很大的工作压力。KB想多花时间和家人在一起，觉得自己“让丈夫和孩子失望”。KB过去3年中因伴随自杀倾向的抑郁症住院2次，曾先后接受安菲

38、他酮(buprobion)和西酞普兰(citalopram)较高剂量和足够疗程治疗重度抑郁，但效果不佳。正在服用的药物：citalopram 60mg qd,simvastatin 20mg qhs,Zolpidem 10mg HS prn.药师建议的抑郁治疗方案？C15,LB,41岁男性，接受抑郁治疗帕罗西汀(paroxetine)20mg/d 12个星期后回到药房取药，告诉药师LB自己感觉心情不错，睡眠也像过去一样不错。然后又和药师低声说最近开始性功能障碍，不知是否和该药引起，如果是，LB要求换药。此时药师向医生建议的用药方案？C16:AK,48岁男性，因中度抑郁住院，这是他去年以来的第3

39、次抑郁发作。正服用舍曲林(sertraline)150mg qd.他妻子说AK经常连续3，4天没有服药，由于需要因为工作旅行时忘记了携带药品。AK成人这种时候自己会变得非常忧虑，而且经常觉得恶心。为解决AK依从性差的问题，药师向医生建议的用药方案是？C17:RH,19岁女性，服用帕罗西汀(paroxetine)40mg qd.她抱怨该药带来过多嗜睡症状，要求换另外一种抗抑郁药。她过去疾病史包括肠易激综合征，经常恶心，甲状腺功能减退症，最近由于饮食失调住院。医生的处方是:安菲他酮(Bupropion)100mg bid,3天后增加剂量。药师看到处方后的建议？C18：WH,31岁女演员,服用丙咪嗪

40、(imipramine)治疗抑郁，抱怨体重增加和身材走样，要求医生换药。药师给医生建议的用药方案为？C19：AO,60岁男性，抑郁症同时有慢性疼痛。正服用的药物有：地高辛(digoxin)1mg qd,lisinopril 40mg/d，药师建议的用药方案？C20：AK，26岁男性，接受西酞普兰(citalopram)40mg qd治疗抑郁效果不佳，尝试过帕罗西汀(paroxetine),舍曲林(sertraline),和万拉法新(venlafaxine),药师建议？C21：JT,37岁女性，互联网公司CEO,年初开始失眠，服用安定已有5个月。因公司业绩问题，工作压力大等原因患抑郁症，药师建议的用药方案?Thank you.