抗抑郁治疗遗传药理学

抗抑郁治疗的遗传药理学1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2DiagnosticCriteriaforMajordepression(DSM-IV)DepressedmoodFeelingsofhopelessness,worthlessnessandguiltInabilitytothinkorconcentrateDiminishedinterestorpleasureDecreasedorincreasedappetiteWeightlossorweightgainInsomniaorhypersominaFatigueorlossofenergyPsychomotorretardationoragitationRecurrentthoughtofdeathorsuicideFive(ormore)oftheabovesymptomsPersistlongerthan2weeksSignificantimpairmentinsocial,occupationalorotherimportantareaoffunctioning抑郁症诊断美国精神障碍诊断与统计手册第4版3DrugtypeMechanismMAOiIrreversibleinhibitionofMAOAandB.TCANonselectiveinhibitionofNA,5-HTanddopaminereuptakeSSRISelectioninhibitionof5-HTreuptakeSNRISelectioninhibitionofNAand5-HTreuptakeNARISelectioninhibitionofNAreuptakeNaSSAEnhancementof5-HTandNAreleasebyblockageofpresynaptic2adrenergicreceptorSARIBlockageof5-HT2receptorandinhibitionof5-HTreuptakeMAOi,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4Relapseratewithdrugvs.placeboincontinuationstudies(DunnerDL.2001JClinPsychiatry)DrugWkofTxRelapse,drug(%)Relapse,placebo(%)PvalueFluoxetine522657<0.01Paroxetine521643<0.001Sertraline441346<0.001Cetalopram241131<0.05Mirtazapine20423<0.05Nefazodone361733<0.00015(GeddesJRetal.2003Lancet)6治疗失败

30-40%部分显效

30-40%显著疗效

35-45%NemeroffCBetal.2002NatNeurosciTsaiSJetal.2003CurrentpharmacogenomicsStimpsonetal.

2003theCochraneDatabaseReview7About30-40%ofMDDpatientsdonotrespondsufficientlytoSSRIs

(TsaiSJetal.Currentpharmacogenomics2003).

Approximately30%ofpeoplesufferingfromclinicallysignificantdepressiveillnessdonotrespondtotheusuallyrecommendeddoseofantidepressants

(Stimpsonetal.theCochraneDatabaseReview2003).Antidepressants:currentlimitations8Thehistoryofgoodresponsetothatagentbyapersonorafamilymember

(SynopsisofPsychiatry.8th).Afamilialtendencytorespondtospecificantidepressantsorantidepressantgroups.

(O’ReillyRLetal.1994BiolPsychiatry)

Geneticfactorsplayasubstantialroleinantidepressantresponse

(TsaiSJetal.Currentpharmacogenomics2003)

(O’ReillyRLetal.1994BiolPsychiatry)

Antidepressants:currentlimitations9Allapprovedclassesofantidepressantsactinoneof

threeways:BlockageofpresynapticmonoaminetransportersInhibitionofmonoamineoxidaseInhibition/excitationofpre/postsynapticreceptorsthatregulatemonoaminetransmitterreleaseand/orneuronalfiringrates(NemeroffCBetal.2002NatNeurosci)

10MAOA-VNTRinpromotor:DRD2Ser311Cys,DRD4exon4VNTR5HT1A

C-1018G,5HT2A

T102C,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,CYP2C9Pharmacogeneticstudiesaboutantidepressantresponsiveness11SelectiveSerotoninReuptakeInhibitorsUseasfirst-linemedicationforMDDFluoxetine(Prozac)wasfirstintroducedin1988,setraline,paroxetine,fluvoxamine,citalopramalsowithsimilarpropertyInhibitingserotoninreuptakebypresynapticneuron60-70%ofMDDpatientsmayresponsetotheSSRI12PharmacogeneticstudiesofAntidepressant:FocusingonSSRIresponse13HeilsAetal.,J.Neurochem.1996Structureofhumanserotonintransportergene14SerotonintransporterpromoterfunctioninhumanJARplacentalchoriocarcinomacell

HeilsAetal.,J.Neurochem.199615SerotonintransporterpromoterfunctioninhumanlymphoblastcellLeschetal.,Science.199616Smeraldietal.,Mol.Psychiatry.1998102(age:30-60,M/F=32/67)patientswithmajordepressivedisorder,baselineHDRS-21>21RandomlyassignedtoFluvoxamine+PlaceboorFluvoxamine+PindololMeasuring21-itemHamiltonDepressionRatingScale(HDRS-21)weeklyfor6weeksPharmacogeneticstudyofSSRIresponseandserotonintransportergeneticvariations17PharmacogeneticstudyofSSRIresponseandserotonintransportergeneticvariationsSmeraldietal.,Mol.Psychiatry.199818Copyrightrestrictionsmayapply.Murphy,G.M.etal.ArchGenPsychiatry2004;61:1163-1169.Survivalcurvesshowingdiscontinuationsduetoadverseeventsforparoxetineandmirtazapine,stratifiedbySerotoninTransporterGenePromoterPolymorphismtypeS:shortform;L:longform%ptsdis-continuingtreatment1920121Majordepressionpatients(age=44.7(16.7),M/F=70/51)treatedwithfluoxetineMeasuringHDRS-21atbaseline(>18)and4thweek.Responder:>=50%decreaseinHDRS-21Remitter:HDRS-21<7at4thweek.21222324MAOA-VNTRinpromotor:DRD2Ser311Cys,DRD4exon4VNTR5HT1A

C-1018G,5HT2A

T102C,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,CYP2C9Pharmacogeneticstudiesaboutantidepressantresponsiveness25ToxiclevelMinimum