精神分裂癥病理機制的研究進展

精神分裂癥病理機制的研究進展和治療學發(fā)展北京大學精神衛(wèi)生研究所周東豐基本病理機制神經(jīng)發(fā)育異常神經(jīng)傳遞異常神經(jīng)退行性變有關發(fā)育異常遺傳和環(huán)境相互作用遺傳方式尚不清楚，多基因遺傳可能性大abnormalgeneINHERITEDDISEASE100%willdeveloptheinheriteddisease(classicalautosomaldominantpattern)4-1StahlSM,EssentialPsychopharmacology(2000)abnormalgeneproductRISKFACTOR1anenzymeistoosloweversincebirthsoitishardtometabolizeneurotransmitterswhenreleaseisveryfastRISKFACTOR2someneuronsmigratedtoofarduringdevelopmentinuteroRISKFACTOR3someofthewrongsynapseswereeliminatedinadolescenceRISKFACTOR4nervesfiretoofastwhenyouseeyourmother1-3areinheritedgenetic“hits”-4&5areenvironmental“hits”expressedthroughabnormalgeneticresponsesRISKFACTOR5nervesfiretoofastwhenyoutake“speed”4-2StahlSM,EssentialPsychopharmacology(2000)LIFEEVENTSFILTERpersonality/copingskillsgeneticvulnerabilityfactorsfordepression4-3StahlSM,EssentialPsychopharmacology(2000)evenifyouinheritthegeneforSchizophrenia,thechancesofwhetherornotyoudevelopthediseasemaybeaffectedbyoutsidefactorsbadchildhooddivorcevirusortoxinschizophrenia4-4StahlSM,EssentialPsychopharmacology(2000)MINORSTRESSORS(DNAwithpredispositionforschizophrenia--highlybiologicallydetermined)SCHIZOPHRENIAMODERATESTRESSORS(DNAwithpredispositionfordepression--moderatelybiologicallydetermined)DEPRESSIONMAJORSTRESSORS(“normal”DNA)PTSD4-5StahlSM,EssentialPsychopharmacology(2000)發(fā)育異常的表現(xiàn)選擇異常遷移異常突觸連接異常goodneuronalselection=healthyneuron=defectiveneuronbadneuronalselection4-6選擇異常badmigrationgoodmigration4-7遷移異常normalDNAnormalDNA正確連線abnormalDNAabnormalDNA錯誤連線4-9StahlSM,Essentialsychopharmacology(2000)神經(jīng)傳遞異常的表現(xiàn)hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)mesolimbicpathway10-8StahlSM,EssentialPsychopharmacology(2000)mesolimbicoveractivity=positivesymptomsofpsychosis10-9StahlSM,EssentialPsychopharmacology(2000)meso-corticalpathway10-10StahlSM,EssentialPsychopharmacology(2000)primarydopaminedeficiencyD2receptorblockadesecondarydopaminedeficiencymesocorticalpathwayincreaseinnegativesymptoms10-11StahlSM,EssentialPsychopharmacology(2000)nigrostriatalpathwaytuberoinfundibularpathwaypositivesymptomspsychoticdepressionbipolarchildhoodpsychoticillnessesschizo-affectiveAlzheimer’s10-2StahlSM,EssentialPsychopharmacology(2000)精神分裂癥的治療機制經(jīng)典抗精神病藥物－純D2受體阻斷劑SDA－DA2/5TH2受體阻斷劑多受體機制藥物DA穩(wěn)定劑D2pureD2blocker11-1經(jīng)典抗精神病藥物pureD2blocker11-2StahlSM,EssentialPsychopharmacology(2000)Increaseinnegativesymptoms11-3StahlSM,EssentialPsychopharmacology(2000)MesocorticalpathwayEPSs11-4StahlSM,EssentialPsychopharmacology(2000)NigrostriatalpathwayBlockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup-regulateThisup-regulationmayleadtotardivedyskinesia11-5StahlSM,EssentialPsychopharmacology(2000)Prolactinlevelsrise11-6StahlSM,EssentialPsychopharmacology(2000)TuberoinfundibularpathwayH1M1D21conventionalantipsychoticdrug11-7StahlSM,EssentialPsychopharmacology(2000)constipationLAXATIVEblurredvisiondrymouthdrowsiness11-8StahlSM,EssentialPsychopharmacology(2000)M1INSERTED=acetylcholine=dopamine11-9StahlSM,EssentialPsychopharmacology(2000)=D2blocker11-10StahlSM,EssentialPsychopharmacology(2000)=anticholinergic11-11StahlSM,EssentialPsychopharmacology(2000)H1INSERTED11-12StahlSM,EssentialPsychopharmacology(2000)drowsinessweightgaindrowsinessdecreasedbloodpressuredizziness11-13StahlSM,EssentialPsychopharmacology(2000)1INSERTED1D2haloperidol11-155HT2AD2SDA11-16SDA5HT7125HT2AD2risperidone11-39StahlSM,EssentialPsychopharmacology(2000)5HT-DAInteractions11-17StahlSM,EssentialPsychopharmacology(2000)Substantianigraraphenucleusbrakebrakeconventionalantipsychoticcaudatenucleus11-25StahlSM,EssentialPsychopharmacology(2000)serotonin-dopamineantagonistcaudatenucleus11-26StahlSM,EssentialPsychopharmacology(2000)conventionalantipsychoticCortex11-28StahlSM,EssentialPsychopharmacology(2000)serotonin-dopamineantagonistCortex11-29StahlSM,EssentialPsychopharmacology(2000)5HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine11-37多受體機制藥物5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine11-40StahlSM,EssentialPsychopharmacology(2000)5HT75HT6H1125HT2AD2quetiapine11-41StahlSM,EssentialPsychopharmacology(2000)AreAntipsychoticswithMultipleTherapeuticMechanismsBetterthanSelectiveDopamine2Antagonists?11-35StahlSM,EssentialPsychopharmacology(2000)multiplemechanisms=sideeffectschlorpromazinesingleselectivemechanisms=lossofsideeffectsHaloperidolmultipletherapeuticmechanisms=improvedefficacyclozapineSDArisperidonequetiapineolanzapineDA部分激動劑或DA穩(wěn)定劑

hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)精神分裂癥的多巴胺假說

高多巴胺通路低多巴胺通路

陽性癥狀陰性癥狀多巴胺部分激動的原理對于多巴胺功能失調(diào)理想的治療

-降低中腦邊緣通路的多巴胺活性

-增強中腦皮質(zhì)通路的多巴胺活性

-不影響結節(jié)漏斗部通路和黑質(zhì)紋狀體通路agonistanxiolyticsedativehypnoticmusclerelaxantanticonvulsantamnesticdependencypartialagonistanxiolyticonlyantagonistnoclinicaleffectpartialinverseagonistpromnestic(memoryenhancing)anxiogenicinverseagonistpromnesticanxiogenicpro-convulsant8-25StahlSM,EssentialPsychopharmacology(2000)FULLAGONIST--lightisatitsbrightest3-15StahlSM,EssentialPsychopharmacology(2000)PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)NOAGONIST--lightisoff3-17StahlSM,EssentialPsychopharmacology(2000)PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)神經(jīng)退行性變凋亡和壞死“pruning”outofcontrolAdiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”4-22DA過度傳遞引起細胞凋亡神經(jīng)退行性變－－細胞死亡GABA神經(jīng)元發(fā)育不足，谷氨酸神經(jīng)元過渡釋放先天因素和后天因素導致免疫過度激活神經(jīng)過度興奮的毒性作用鈣離子大量內(nèi)流自由基大量生成細胞死亡abnormalgeneproduct10-18StahlSM,EssentialPsychopharmacology(2000)overexcitationduetoglutamate10-27StahlSM,EssentialPsychopharmacology(2000)excesscalciumactivatesenzyme10-28StahlSM,EssentialPsychopharmacology(2000)enzymeproducesfreeradicaltheendisnear10-29StahlSM,EssentialPsychopharmacology(2000)freeradicalsbegindestroyingthecell10-30StahlSM,EssentialPsychopharmacology(2000)finally,freeradicalsdestroythecell10-31StahlSM,EssentialPsychopharmacology(2000)10-20StahlSM,EssentialPsychopharmacology(2000)apoptosis/necrosis100%50%015204060精神分裂癥治療藥物治療，主要改變傳遞異常，不能改變發(fā)育異常和阻斷退行性變針對退行性變的非抗精神病藥物治療免疫調(diào)節(jié)劑自由基俘獲劑或清除劑非藥物治療免疫異常和免疫調(diào)節(jié)劑治療既往研究發(fā)現(xiàn)精神分裂癥免疫過度激活Decreasedproductionofinterleukin-2(IL-2),IL-2secretingcellsandCD4+cellsinmedication-freepatientswithschizophrenia

(Zhang,Zhouetal,JournalofPsychiatricResearch2002)研究發(fā)現(xiàn)精神分裂癥患者存在IL-2產(chǎn)物生成降低，與T細胞數(shù)目減少，IL-2分泌減少有關

Elevatedinterleukin-2,interleukin-6andinterleukin-8serumlevelsinneuroleptic-freeschizophrenia:associationwithpsychopathology(Zhang,Zhouetal,SchizophreniaResearch2002)研究進一步發(fā)現(xiàn)未服抗精神病藥物的不同亞型精神分裂癥患者細胞因子改變不同Changesinseruminterleukin-2,-6,and-8levelsbeforeandduringtreatmentwithrisperidoneandhaloperidol:relationshiptooutcomeinschizophrenia(Zhang,Zhouetal,JournalofClinicalPsychiatry2004)典型和非典型抗精神病藥物均部分改善精神分裂癥患者的細胞因子異常，且基線的細胞因子水平可預測藥物療效CortisolandCytokinesinChronicandTreatment-ResistantPatientswithSchizophrenia:AssociationwithPsychopathologyandResponsetoAntipsychotics(Zhang,Zhouetal,Neuropsychopharmacology2005)未服抗精神病藥物的患者細胞因子的改變與其HPA軸功能紊亂相關，且經(jīng)過藥物治療改善后這些改變趨于正常，提示這些改變是癥狀相關的Tumournecrosisfactoralphapolymorphism(-1031T/C)isassociatedwithageofonsetofschizophrenia.(Zhangetal,MolecularPsychiatry2005)腫瘤壞死因子－alpha基因11031T/C多態(tài)性與早發(fā)型精神分裂癥有關其他相關論文免疫調(diào)節(jié)劑治療精神分裂癥的研究接受利培酮治療的首發(fā)精神分裂癥celecoxib增效作用的雙盲對照研究Adouble-blind,Placebo-controlledtrialofcelecoxibaddedtorisperidoneintreatment-na?ve,Firstepisodepatientswithschizophrenia(Grant:03T-459)，2003～2006;青蒿素對精神分裂癥的增效作用研究Adouble-blind,placebo-controlledtrialofartemisininaddedtorisperidoneintreatment-na?ve,firstepisodepatientswithschizophrenia(Grant#:05T-726)，2006～2009.1、YLTan,DFZhou,XYZhang.Decreasedplasmabrain-derivedneurotrophicfactorlevelsinschizophrenicpatientswithtardivedyskinesia:associationwithdyskineticmovements.SchizophreniaResearch,2005,74(2-3):176-183.（IF=4.072，2003）2、YLTan,DFZhou,LYCao,YZZou,XYZhang.DecreasedBDNFinserumofpatientswithchronicschizophren