精神分裂癥病理機制的研究進展演示文稿

精神分裂癥病理機制的研究進展演示文稿當前第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前第2頁\共有98頁\編于星期五\11點有關發(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當前第3頁\共有98頁\編于星期五\11點abnormalgeneINHERITEDDISEASE100%willdeveloptheinheriteddisease(classicalautosomaldominantpattern)4-1StahlSM,EssentialPsychopharmacology(2000)abnormalgeneproduct當前第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)當前第5頁\共有98頁\編于星期五\11點LIFEEVENTSFILTERpersonality/copingskillsgeneticvulnerabilityfactorsfordepression4-3StahlSM,EssentialPsychopharmacology(2000)當前第6頁\共有98頁\編于星期五\11點evenifyouinheritthegeneforSchizophrenia,thechancesofwhetherornotyoudevelopthediseasemaybeaffectedbyoutsidefactorsbadchildhooddivorcevirusortoxinschizophrenia4-4StahlSM,EssentialPsychopharmacology(2000)當前第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前第9頁\共有98頁\編于星期五\11點goodneuronalselection=healthyneuron=defectiveneuronbadneuronalselection4-6選擇異常當前第10頁\共有98頁\編于星期五\11點badmigrationgoodmigration4-7遷移異常當前第11頁\共有98頁\編于星期五\11點normalDNAnormalDNA當前第12頁\共有98頁\編于星期五\11點正確連線當前第13頁\共有98頁\編于星期五\11點abnormalDNAabnormalDNA當前第14頁\共有98頁\編于星期五\11點錯誤連線4-9StahlSM,Essentialsychopharmacology(2000)當前第15頁\共有98頁\編于星期五\11點神經傳遞異常的表現(xiàn)當前第16頁\共有98頁\編于星期五\11點hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)當前第17頁\共有98頁\編于星期五\11點mesolimbicpathway10-8StahlSM,EssentialPsychopharmacology(2000)當前第18頁\共有98頁\編于星期五\11點mesolimbicoveractivity=positivesymptomsofpsychosis10-9StahlSM,EssentialPsychopharmacology(2000)當前第19頁\共有98頁\編于星期五\11點meso-corticalpathway10-10StahlSM,EssentialPsychopharmacology(2000)當前第20頁\共有98頁\編于星期五\11點primarydopaminedeficiencyD2receptorblockadesecondarydopaminedeficiencymesocorticalpathwayincreaseinnegativesymptoms10-11StahlSM,EssentialPsychopharmacology(2000)當前第21頁\共有98頁\編于星期五\11點nigrostriatalpathway當前第22頁\共有98頁\編于星期五\11點tuberoinfundibularpathway當前第23頁\共有98頁\編于星期五\11點positivesymptomspsychoticdepressionbipolarchildhoodpsychoticillnessesschizo-affectiveAlzheimer’s10-2StahlSM,EssentialPsychopharmacology(2000)當前第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)定劑當前第25頁\共有98頁\編于星期五\11點D2pureD2blocker11-1經典抗精神病藥物當前第26頁\共有98頁\編于星期五\11點pureD2blocker11-2StahlSM,EssentialPsychopharmacology(2000)當前第27頁\共有98頁\編于星期五\11點Increaseinnegativesymptoms11-3StahlSM,EssentialPsychopharmacology(2000)Mesocorticalpathway當前第28頁\共有98頁\編于星期五\11點EPSs11-4StahlSM,EssentialPsychopharmacology(2000)Nigrostriatalpathway當前第29頁\共有98頁\編于星期五\11點Blockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup-regulateThisup-regulationmayleadtotardivedyskinesia11-5StahlSM,EssentialPsychopharmacology(2000)當前第30頁\共有98頁\編于星期五\11點Prolactinlevelsrise11-6StahlSM,EssentialPsychopharmacology(2000)Tuberoinfundibularpathway當前第31頁\共有98頁\編于星期五\11點H1M1D21conventionalantipsychoticdrug11-7StahlSM,EssentialPsychopharmacology(2000)當前第32頁\共有98頁\編于星期五\11點constipationLAXATIVEblurredvisiondrymouthdrowsiness11-8StahlSM,EssentialPsychopharmacology(2000)M1INSERTED當前第33頁\共有98頁\編于星期五\11點=acetylcholine=dopamine11-9StahlSM,EssentialPsychopharmacology(2000)當前第34頁\共有98頁\編于星期五\11點=D2blocker11-10StahlSM,EssentialPsychopharmacology(2000)當前第35頁\共有98頁\編于星期五\11點=anticholinergic11-11StahlSM,EssentialPsychopharmacology(2000)當前第36頁\共有98頁\編于星期五\11點H1INSERTED11-12StahlSM,EssentialPsychopharmacology(2000)drowsinessweightgain當前第37頁\共有98頁\編于星期五\11點drowsinessdecreasedbloodpressuredizziness11-13StahlSM,EssentialPsychopharmacology(2000)1INSERTED當前第38頁\共有98頁\編于星期五\11點1D2haloperidol11-15當前第39頁\共有98頁\編于星期五\11點5HT2AD2SDA11-16SDA當前第40頁\共有98頁\編于星期五\11點5HT7125HT2AD2risperidone11-39StahlSM,EssentialPsychopharmacology(2000)當前第41頁\共有98頁\編于星期五\11點5HT-DAInteractions11-17StahlSM,EssentialPsychopharmacology(2000)Substantianigraraphenucleusbrakebrake當前第42頁\共有98頁\編于星期五\11點conventionalantipsychoticcaudatenucleus11-25StahlSM,EssentialPsychopharmacology(2000)當前第43頁\共有98頁\編于星期五\11點serotonin-dopamineantagonistcaudatenucleus11-26StahlSM,EssentialPsychopharmacology(2000)當前第44頁\共有98頁\編于星期五\11點conventionalantipsychoticCortex11-28StahlSM,EssentialPsychopharmacology(2000)當前第45頁\共有98頁\編于星期五\11點serotonin-dopamineantagonistCortex11-29StahlSM,EssentialPsychopharmacology(2000)當前第46頁\共有98頁\編于星期五\11點5HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine11-37多受體機制藥物當前第47頁\共有98頁\編于星期五\11點5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine11-40StahlSM,EssentialPsychopharmacology(2000)當前第48頁\共有98頁\編于星期五\11點5HT75HT6H1125HT2AD2quetiapine11-41StahlSM,EssentialPsychopharmacology(2000)當前第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

當前第51頁\共有98頁\編于星期五\11點hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)當前第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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增強中腦皮質通路的多巴胺活性

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不影響結節(jié)漏斗部通路和黑質紋狀體通路當前第54頁\共有98頁\編于星期五\11點agonistanxiolyticsedativehypnoticmusclerelaxantanticonvulsantamnesticdependencypartialagonistanxiolyticonlyantagonistnoclinicaleffectpartialinverseagonistpromnestic(memoryenhancing)anxiogenicinverseagonistpromnesticanxiogenicpro-convulsant8-25StahlSM,EssentialPsychopharmacology(2000)當前第55頁\共有98頁\編于星期五\11點FULLAGONIST--lightisatitsbrightest3-15StahlSM,EssentialPsychopharmacology(2000)當前第56頁\共有98頁\編于星期五\11點PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)當前第57頁\共有98頁\編于星期五\11點NOAGONIST--lightisoff3-17StahlSM,EssentialPsychopharmacology(2000)當前第58頁\共有98頁\編于星期五\11點PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)當前第59頁\共有98頁\編于星期五\11點神經退行性變凋亡和壞死當前第60頁\共有98頁\編于星期五\11點“pruning”outofcontrolAdiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”4-22DA過度傳遞引起細胞凋亡當前第61頁\共有98頁\編于星期五\11點神經退行性變－－細胞死亡GABA神經元發(fā)育不足，谷氨酸神經元過渡釋放先天因素和后天因素導致免疫過度激活神經過度興奮的毒性作用鈣離子大量內流自由基大量生成細胞死亡當前第62頁\共有98頁\編于星期五\11點abnormalgeneproduct10-18StahlSM,EssentialPsychopharmacology(2000)當前第63頁\共有98頁\編于星期五\11點overexcitationduetoglutamate10-27StahlSM,EssentialPsychopharmacology(2000)當前第64頁\共有98頁\編于星期五\11點excesscalciumactivatesenzyme10-28StahlSM,EssentialPsychopharmacology(2000)當前第65頁\共有98頁\編于星期五\11點enzymeproducesfreeradicaltheendisnear10-29StahlSM,EssentialPsychopharmacology(2000)當前第66頁\共有98頁\編于星期五\11點freeradicalsbegindestroyingthecell10-30StahlSM,EssentialPsychopharmacology(2000)當前第67頁\共有98頁\編于星期五\11點finally,freeradicalsdestroythecell10-31StahlSM,EssentialPsychopharmacology(2000)當前第68頁\共有98頁\編于星期五\11點10-20StahlSM,EssentialPsychopharmacology(2000)apoptosis/necrosis100%50%015204060當前第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節(jié)劑自由基俘獲劑或清除劑非藥物治療當前第70頁\共有98頁\編于星期五\11點免疫異常和免疫調節(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產物生成降低，與T細胞數(shù)目減少，IL-2分泌減少有關當前第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胞因子改變不同當前第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胞因子異常，且基線的細胞因子水平可預測藥物療效當前第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胞因子的改變與其HPA軸功能紊亂相關，且經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當前第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)型精神分裂癥有關當前第76頁\共有98頁\編于星期五\11點其他相關論文當前第77頁\共有98頁\編于星期五\11點當前第78頁\共有98頁\編于星期五\11點免疫調節(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.當前第79頁\共有98頁\編于星期五\11點當前第80頁\共有98頁\編于星期五\11點當前第81頁\共有98頁\編于星期五\11點當前第82頁\共有98頁\編于星期五\11點當前第83頁\共有98頁\編于星期五\11點當前第84頁\共有98頁\編于星期五\11點當前第85頁\共有98頁\編于星期五\11點當前第86頁\共有98頁\編于星期五\11點當前第87頁\共有98頁\編于星期五\11點當前第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