精神分裂癥病理機制的研究進展演示文稿當(dāng)前第1頁\共有98頁\編于星期五\11點（優(yōu)選）精神分裂癥病理機制的研究進展當(dāng)前第2頁\共有98頁\編于星期五\11點有關(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當(dāng)前第3頁\共有98頁\編于星期五\11點abnormalgeneINHERITEDDISEASE100%willdeveloptheinheriteddisease(classicalautosomaldominantpattern)4-1StahlSM,EssentialPsychopharmacology(2000)abnormalgeneproduct當(dāng)前第4頁\共有98頁\編于星期五\11點RISKFACTOR1anenzymeistoosloweversincebirthsoitishardtometabolizeneurotransmitterswhenreleaseisveryfastRISKFACTOR2someneuronsmigratedtoofarduringdevelopmentinuteroRISKFACTOR3someofthewrongsynapseswereeliminatedinadolescenceRISKFACTOR4nervesfiretoofastwhenyouseeyourmother1-3areinheritedgenetic“hits”-4&5areenvironmental“hits”expressedthroughabnormalgeneticresponsesRISKFACTOR5nervesfiretoofastwhenyoutake“speed”4-2StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第5頁\共有98頁\編于星期五\11點LIFEEVENTSFILTERpersonality/copingskillsgeneticvulnerabilityfactorsfordepression4-3StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第6頁\共有98頁\編于星期五\11點evenifyouinheritthegeneforSchizophrenia,thechancesofwhetherornotyoudevelopthediseasemaybeaffectedbyoutsidefactorsbadchildhooddivorcevirusortoxinschizophrenia4-4StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第7頁\共有98頁\編于星期五\11點MINORSTRESSORS(DNAwithpredispositionforschizophrenia--highlybiologicallydetermined)SCHIZOPHRENIAMODERATESTRESSORS(DNAwithpredispositionfordepression--moderatelybiologicallydetermined)DEPRESSIONMAJORSTRESSORS(“normal”DNA)PTSD4-5StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第8頁\共有98頁\編于星期五\11點發(fā)育異常的表現(xiàn)選擇異常遷移異常突觸連接異常當(dāng)前第9頁\共有98頁\編于星期五\11點goodneuronalselection=healthyneuron=defectiveneuronbadneuronalselection4-6選擇異常當(dāng)前第10頁\共有98頁\編于星期五\11點badmigrationgoodmigration4-7遷移異常當(dāng)前第11頁\共有98頁\編于星期五\11點normalDNAnormalDNA當(dāng)前第12頁\共有98頁\編于星期五\11點正確連線當(dāng)前第13頁\共有98頁\編于星期五\11點abnormalDNAabnormalDNA當(dāng)前第14頁\共有98頁\編于星期五\11點錯誤連線4-9StahlSM,Essentialsychopharmacology(2000)當(dāng)前第15頁\共有98頁\編于星期五\11點神經(jīng)傳遞異常的表現(xiàn)當(dāng)前第16頁\共有98頁\編于星期五\11點hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第17頁\共有98頁\編于星期五\11點mesolimbicpathway10-8StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第18頁\共有98頁\編于星期五\11點mesolimbicoveractivity=positivesymptomsofpsychosis10-9StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第19頁\共有98頁\編于星期五\11點meso-corticalpathway10-10StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第20頁\共有98頁\編于星期五\11點primarydopaminedeficiencyD2receptorblockadesecondarydopaminedeficiencymesocorticalpathwayincreaseinnegativesymptoms10-11StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第21頁\共有98頁\編于星期五\11點nigrostriatalpathway當(dāng)前第22頁\共有98頁\編于星期五\11點tuberoinfundibularpathway當(dāng)前第23頁\共有98頁\編于星期五\11點positivesymptomspsychoticdepressionbipolarchildhoodpsychoticillnessesschizo-affectiveAlzheimer’s10-2StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第24頁\共有98頁\編于星期五\11點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)定劑當(dāng)前第25頁\共有98頁\編于星期五\11點D2pureD2blocker11-1經(jīng)典抗精神病藥物當(dāng)前第26頁\共有98頁\編于星期五\11點pureD2blocker11-2StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第27頁\共有98頁\編于星期五\11點Increaseinnegativesymptoms11-3StahlSM,EssentialPsychopharmacology(2000)Mesocorticalpathway當(dāng)前第28頁\共有98頁\編于星期五\11點EPSs11-4StahlSM,EssentialPsychopharmacology(2000)Nigrostriatalpathway當(dāng)前第29頁\共有98頁\編于星期五\11點Blockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup-regulateThisup-regulationmayleadtotardivedyskinesia11-5StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第30頁\共有98頁\編于星期五\11點Prolactinlevelsrise11-6StahlSM,EssentialPsychopharmacology(2000)Tuberoinfundibularpathway當(dāng)前第31頁\共有98頁\編于星期五\11點H1M1D21conventionalantipsychoticdrug11-7StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第32頁\共有98頁\編于星期五\11點constipationLAXATIVEblurredvisiondrymouthdrowsiness11-8StahlSM,EssentialPsychopharmacology(2000)M1INSERTED當(dāng)前第33頁\共有98頁\編于星期五\11點=acetylcholine=dopamine11-9StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第34頁\共有98頁\編于星期五\11點=D2blocker11-10StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第35頁\共有98頁\編于星期五\11點=anticholinergic11-11StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第36頁\共有98頁\編于星期五\11點H1INSERTED11-12StahlSM,EssentialPsychopharmacology(2000)drowsinessweightgain當(dāng)前第37頁\共有98頁\編于星期五\11點drowsinessdecreasedbloodpressuredizziness11-13StahlSM,EssentialPsychopharmacology(2000)1INSERTED當(dāng)前第38頁\共有98頁\編于星期五\11點1D2haloperidol11-15當(dāng)前第39頁\共有98頁\編于星期五\11點5HT2AD2SDA11-16SDA當(dāng)前第40頁\共有98頁\編于星期五\11點5HT7125HT2AD2risperidone11-39StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第41頁\共有98頁\編于星期五\11點5HT-DAInteractions11-17StahlSM,EssentialPsychopharmacology(2000)Substantianigraraphenucleusbrakebrake當(dāng)前第42頁\共有98頁\編于星期五\11點conventionalantipsychoticcaudatenucleus11-25StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第43頁\共有98頁\編于星期五\11點serotonin-dopamineantagonistcaudatenucleus11-26StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第44頁\共有98頁\編于星期五\11點conventionalantipsychoticCortex11-28StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第45頁\共有98頁\編于星期五\11點serotonin-dopamineantagonistCortex11-29StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第46頁\共有98頁\編于星期五\11點5HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine11-37多受體機制藥物當(dāng)前第47頁\共有98頁\編于星期五\11點5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine11-40StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第48頁\共有98頁\編于星期五\11點5HT75HT6H1125HT2AD2quetiapine11-41StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第49頁\共有98頁\編于星期五\11點AreAntipsychoticswithMultipleTherapeuticMechanismsBetterthanSelectiveDopamine2Antagonists?11-35StahlSM,EssentialPsychopharmacology(2000)multiplemechanisms=sideeffectschlorpromazinesingleselectivemechanisms=lossofsideeffectsHaloperidolmultipletherapeuticmechanisms=improvedefficacyclozapineSDArisperidonequetiapineolanzapine當(dāng)前第50頁\共有98頁\編于星期五\11點DA部分激動劑或DA穩(wěn)定劑

當(dāng)前第51頁\共有98頁\編于星期五\11點hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第52頁\共有98頁\編于星期五\11點精神分裂癥的多巴胺假說

高多巴胺通路低多巴胺通路

陽性癥狀陰性癥狀當(dāng)前第53頁\共有98頁\編于星期五\11點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

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增強中腦皮質(zhì)通路的多巴胺活性

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不影響結(jié)節(jié)漏斗部通路和黑質(zhì)紋狀體通路當(dāng)前第54頁\共有98頁\編于星期五\11點agonistanxiolyticsedativehypnoticmusclerelaxantanticonvulsantamnesticdependencypartialagonistanxiolyticonlyantagonistnoclinicaleffectpartialinverseagonistpromnestic(memoryenhancing)anxiogenicinverseagonistpromnesticanxiogenicpro-convulsant8-25StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第55頁\共有98頁\編于星期五\11點FULLAGONIST--lightisatitsbrightest3-15StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第56頁\共有98頁\編于星期五\11點PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第57頁\共有98頁\編于星期五\11點NOAGONIST--lightisoff3-17StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第58頁\共有98頁\編于星期五\11點PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第59頁\共有98頁\編于星期五\11點神經(jīng)退行性變凋亡和壞死當(dāng)前第60頁\共有98頁\編于星期五\11點“pruning”outofcontrolAdiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”4-22DA過度傳遞引起細(xì)胞凋亡當(dāng)前第61頁\共有98頁\編于星期五\11點神經(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內(nèi)流自由基大量生成細(xì)胞死亡當(dāng)前第62頁\共有98頁\編于星期五\11點abnormalgeneproduct10-18StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第63頁\共有98頁\編于星期五\11點overexcitationduetoglutamate10-27StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第64頁\共有98頁\編于星期五\11點excesscalciumactivatesenzyme10-28StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第65頁\共有98頁\編于星期五\11點enzymeproducesfreeradicaltheendisnear10-29StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第66頁\共有98頁\編于星期五\11點freeradicalsbegindestroyingthecell10-30StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第67頁\共有98頁\編于星期五\11點finally,freeradicalsdestroythecell10-31StahlSM,EssentialPsychopharmacology(2000)當(dāng)前第68頁\共有98頁\編于星期五\11點10-20StahlSM,EssentialPsychopharmacology(2000)apoptosis/necrosis100%50%015204060當(dāng)前第69頁\共有98頁\編于星期五\11點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當(dāng)前第70頁\共有98頁\編于星期五\11點免疫異常和免疫調(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當(dāng)前第71頁\共有98頁\編于星期五\11點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)當(dāng)前第72頁\共有98頁\編于星期五\11點

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(xì)胞因子改變不同當(dāng)前第73頁\共有98頁\編于星期五\11點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)測藥物療效當(dāng)前第74頁\共有98頁\編于星期五\11點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)的當(dāng)前第75頁\共有98頁\編于星期五\11點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)當(dāng)前第76頁\共有98頁\編于星期五\11點其他相關(guān)論文當(dāng)前第77頁\共有98頁\編于星期五\11點當(dāng)前第78頁\共有98頁\編于星期五\11點免疫調(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.當(dāng)前第79頁\共有98頁\編于星期五\11點當(dāng)前第80頁\共有98頁\編于星期五\11點當(dāng)前第81頁\共有98頁\編于星期五\11點當(dāng)前第82頁\共有98頁\編于星期五\11點當(dāng)前第83頁\共有98頁\編于星期五\11點當(dāng)前第84頁\共有98頁\編于星期五\11點當(dāng)前第85頁\共有98頁\編于星期五\11點當(dāng)前第86頁\共有98頁\編于星期五\11點當(dāng)前第87頁\共有98頁\編于星期五\11點當(dāng)前第88頁\共有98頁\編于星期五\11點1、YLTan,DFZhou,XYZhang.Decreasedplasmabrain-derivedneurotrophicfactorlevelsinschizophrenicpatientswithtardivedyskinesia:associationwithdyskineticmovements.SchizophreniaResearch,2005,74(2-3):176-183.（IF=4.072，2003）2、YLTan,DFZhou,LYCao,YZZou,XYZhang.DecreasedBDNFinserumofpatientswithchronicschizophreniaonlong-termtreatmentwithantipsychatics,NeuroscienceLetters,2005,382(6):27-32.（IF=1.996，2003）3、YLTan,DFZhou,LYCao,YZZou,XYZhang.AssociationbetweentheBDNFC270Tpolymorphismandnegativesymptomsofschizophrenia.SchizophreniaResearch.2005,77:355-356.（IF=4.072，2003）4、YLTan,DFZhou,LYCao,YZZou,XYZhang.EffrctoftheBDNFVal66Metgenotypeonepisoticmemoryinschizophrenia.SchizophreniaResearch.2005(inpress).（IF=4.072，2003）當(dāng)前第89頁\共有98頁\編于星期五\11點5、譚云龍，周東豐，張向陽等．遲發(fā)性運動障礙患者血漿超氧化物歧化酶、過氧化化氫酶、谷胱苷肽過氧化物酶活性及丙二醛水平的改變．中華精神科雜志，2005，38（3）：166－168．

6、譚云龍，周東豐，鄒義壯等．遲發(fā)性運動障礙患者血清泌乳素濃度分析．中國心理衛(wèi)生雜志，2005,19（7）：463－466．7、譚云龍，周東豐，鄒義壯．維生素E對遲發(fā)性運動障礙模型大鼠的影響．中華精神科雜志，2004，37