精神分裂癥病理機(jī)制的研究進(jìn)展

精神分裂癥病理機(jī)制的研究進(jìn)展和治療學(xué)發(fā)展北京大學(xué)精神衛(wèi)生研究所周東豐基本病理機(jī)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(guān)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(cuò)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(jī)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(jī)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(jī)制藥物5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine11-40StahlSM,EssentialPsychopharmacology(2000)5HT75HT6H1125HT2AD2quetiapine11-41StahlSM,EssentialPsychopharmacology(2000)AreAntipsychoticswithMultipleTherapeuticMechanismsBetterthanSelectiveDopamine2Antagonists?11-35StahlSM,EssentialPsychopharmacology(2000)multiplemechanisms=sideeffectschlorpromazinesingleselectivemechanisms=lossofsideeffectsHaloperidolmultipletherapeuticmechanisms=improvedefficacyclozapineSDArisperidonequetiapineolanzapineDA部分激動(dòng)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(dòng)的原理對(duì)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(qiáng)中腦皮質(zhì)通路的多巴胺活性

-不影響結(jié)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(xì)胞凋亡神經(jīng)退行性變－－細(xì)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(dǎo)致免疫過度激活神經(jīng)過度興奮的毒性作用鈣離子大量?jī)?nèi)流自由基大量生成細(xì)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(duì)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(xì)胞數(shù)目減少，IL-2分泌減少有關(guān)

Elevatedinterleukin-2,interleukin-6andinterleukin-8serumlevelsinneuroleptic-freeschizophrenia:associationwithpsychopathology(Zhang,Zhouetal,SchizophreniaResearch2002)研究進(jìn)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(xì)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(xì)胞因子異常，且基線的細(xì)胞因子水平可預(yù)測(cè)藥物療效CortisolandCytokinesinChronicandTreatment-ResistantPatientswithSchizophrenia:AssociationwithPsychopathologyandResponsetoAntipsychotics(Zhang,Zhouetal,Neuropsychopharmacology2005)未服抗精神病藥物的患者細(xì)胞因子的改變與其HPA軸功能紊亂相關(guān)，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(guān)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(guān)其他相關(guān)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(duì)照研究Adouble-blind,Placebo-controlledtrialofcelecoxibaddedtorisperidoneintreatment-na?ve,Firstepisodepatientswithschizophrenia(Grant:03T-459)，2003～2006;青蒿素對(duì)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