抗抑郁治疗的遗传药理学.ppt

抗抑郁治疗的遗传药理学 王连生 抑郁症的终身患病率为10 20 时点患病率为2 5 在世界十大常见疾病中该病排行第四 预计在2020年 抑郁障碍在疾病总负担中位居第二 抑郁症流行情况 抑郁症诊断美国精神障碍诊断与统计手册第4版 MAOi monoamineoxidaseinhibitors SSRIselective5 HTreuptakeinhibitors SNRI 5 HTandNAreuptakeinhibitors NARI NAuptakeinhibitors NaSSA noradrenergicandspecific5 HTantidepressants SARI 5 HTantagonistandreuptakeinhibitors 临床上治疗药物 中国精神障碍分类与诊断标准第3版 CCMD 3 推荐一线药物 Relapseratewithdrugvs placeboincontinuationstudies DunnerDL 2001JClinPsychiatry GeddesJRetal 2003Lancet 治疗失败30 40 部分显效30 40 显著疗效35 45 NemeroffCBetal 2002NatNeurosciTsaiSJetal 2003CurrentpharmacogenomicsStimpsonetal 2003theCochraneDatabaseReview About30 40 ofMDDpatientsdonotrespondsufficientlytoSSRIs TsaiSJetal Currentpharmacogenomics2003 Approximately30 ofpeoplesufferingfromclinicallysignificantdepressiveillnessdonotrespondtotheusuallyrecommendeddoseofantidepressants Stimpsonetal theCochraneDatabaseReview2003 Antidepressants currentlimitations Thehistoryofgoodresponsetothatagentbyapersonorafamilymember SynopsisofPsychiatry 8th Afamilialtendencytorespondtospecificantidepressantsorantidepressantgroups O ReillyRLetal 1994BiolPsychiatry Geneticfactorsplayasubstantialroleinantidepressantresponse TsaiSJetal Currentpharmacogenomics2003 O ReillyRLetal 1994BiolPsychiatry Antidepressants currentlimitations Allapprovedclassesofantidepressantsactinoneofthreeways BlockageofpresynapticmonoaminetransportersInhibitionofmonoamineoxidaseInhibition excitationofpre postsynapticreceptorsthatregulatemonoaminetransmitterreleaseand orneuronalfiringrates NemeroffCBetal 2002NatNeurosci MAOA VNTRinpromotor DRD2Ser311Cys DRD4exon4VNTR5HT1AC 1018G 5HT2AT102C 5HT2AG 1438A 5HT2C 5HT6T267C ACEI D G protein 3C825TADRB1G1165CNOS1C276T IL 1 C 511T BDNFV66M 脑源神经营养因子 Phase IIenzymesCYP1A2 CYP2B6 CYP3A4 CYP2D6 CYP2C19 CYP2C9 Pharmacogeneticstudiesaboutantidepressantresponsiveness SelectiveSerotoninReuptakeInhibitors Useasfirst linemedicationforMDDFluoxetine Prozac wasfirstintroducedin1988 setraline paroxetine fluvoxamine citalopramalsowithsimilarpropertyInhibitingserotoninreuptakebypresynapticneuron60 70 ofMDDpatientsmayresponsetotheSSRI PharmacogeneticstudiesofAntidepressant FocusingonSSRIresponse HeilsAetal J Neurochem 1996 Structureofhumanserotonintransportergene SerotonintransporterpromoterfunctioninhumanJARplacentalchoriocarcinomacell HeilsAetal J Neurochem 1996 Serotonintransporterpromoterfunctioninhumanlymphoblastcell Leschetal Science 1996 Smeraldietal Mol Psychiatry 1998102 age 30 60 M F 32 67 patientswithmajordepressivedisorder baselineHDRS 21 21RandomlyassignedtoFluvoxamine PlaceboorFluvoxamine PindololMeasuring21 itemHamiltonDepressionRatingScale HDRS 21 weeklyfor6weeks PharmacogeneticstudyofSSRIresponseandserotonintransportergeneticvariations PharmacogeneticstudyofSSRIresponseandserotonintransportergeneticvariations Smeraldietal Mol Psychiatry 1998 Copyrightrestrictionsmayapply Murphy G M etal ArchGenPsychiatry2004 61 1163 1169 Survivalcurvesshowingdiscontinuationsduetoadverseeventsforparoxetineandmirtazapine stratifiedbySerotoninTransporterGenePromoterPolymorphismtypeS shortform L longform ptsdis continuingtreatment 121Majordepressionpatients age 44 7 16 7 M F 70 51 treatedwithfluoxetineMeasuringHDRS 21atbaseline 18 and4thweek Responder 50 decreaseinHDRS 21Remitter HDRS 21 7at4thweek MAOA VNTRinpromotor DRD2Ser311Cys DRD4exon4VNTR5HT1AC 1018G 5HT2AT102C 5HT2AG 1438A 5HT2C 5HT6T267C ACEI D G protein 3C825TADRB1G1165CNOS1C276T IL 1 C 511T BDNFV66M 脑源神经营养因子 Phase IIenzymesCYP1A2 CYP2B6 CYP3A4 CYP2D6 CYP2C19 CYP2C9 Pharmacogeneticstudiesaboutantidepressantresponsiveness Toxiclevel Minimumtherapeuticlevel Cp time Therapeuticwindow F DoseClearance T T dosinginterval Css Amitriptyline阿米替林Citalopram西酞普兰Desipramine地昔帕明Doxepin多虑平Duloxetine度洛西汀Fluoxetine氟西汀Fluvoxamine氟伏沙明Imipramine丙咪嗪Maprotiline马普替林Mianserin米安色林Mirtazapine米氮平Moclobemide吗氯贝胺 Nefazod