精神分裂症病理机制的研究进展演示文稿

精神分裂症病理机制的研究进展演示文稿当前1页，总共98页。（优选）精神分裂症病理机制的研究进展当前2页，总共98页。有关发育异常遗传和环境相互作用遗传方式尚不清楚，多基因遗传可能性大当前3页，总共98页。abnormalgeneINHERITEDDISEASE100%willdeveloptheinheriteddisease(classicalautosomaldominantpattern)4-1StahlSM,EssentialPsychopharmacology(2000)abnormalgeneproduct当前4页，总共98页。RISKFACTOR1anenzymeistoosloweversincebirthsoitishardtometabolizeneurotransmitterswhenreleaseisveryfastRISKFACTOR2someneuronsmigratedtoofarduringdevelopmentinuteroRISKFACTOR3someofthewrongsynapseswereeliminatedinadolescenceRISKFACTOR4nervesfiretoofastwhenyouseeyourmother1-3areinheritedgenetic“hits”-4&5areenvironmental“hits”expressedthroughabnormalgeneticresponsesRISKFACTOR5nervesfiretoofastwhenyoutake“speed”4-2StahlSM,EssentialPsychopharmacology(2000)当前5页，总共98页。LIFEEVENTSFILTERpersonality/copingskillsgeneticvulnerabilityfactorsfordepression4-3StahlSM,EssentialPsychopharmacology(2000)当前6页，总共98页。evenifyouinheritthegeneforSchizophrenia,thechancesofwhetherornotyoudevelopthediseasemaybeaffectedbyoutsidefactorsbadchildhooddivorcevirusortoxinschizophrenia4-4StahlSM,EssentialPsychopharmacology(2000)当前7页，总共98页。MINORSTRESSORS(DNAwithpredispositionforschizophrenia--highlybiologicallydetermined)SCHIZOPHRENIAMODERATESTRESSORS(DNAwithpredispositionfordepression--moderatelybiologicallydetermined)DEPRESSIONMAJORSTRESSORS(“normal”DNA)PTSD4-5StahlSM,EssentialPsychopharmacology(2000)当前8页，总共98页。发育异常的表现选择异常迁移异常突触连接异常当前9页，总共98页。goodneuronalselection=healthyneuron=defectiveneuronbadneuronalselection4-6选择异常当前10页，总共98页。badmigrationgoodmigration4-7迁移异常当前11页，总共98页。normalDNAnormalDNA当前12页，总共98页。正确连线当前13页，总共98页。abnormalDNAabnormalDNA当前14页，总共98页。错误连线4-9StahlSM,Essentialsychopharmacology(2000)当前15页，总共98页。神经传递异常的表现当前16页，总共98页。hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)当前17页，总共98页。mesolimbicpathway10-8StahlSM,EssentialPsychopharmacology(2000)当前18页，总共98页。mesolimbicoveractivity=positivesymptomsofpsychosis10-9StahlSM,EssentialPsychopharmacology(2000)当前19页，总共98页。meso-corticalpathway10-10StahlSM,EssentialPsychopharmacology(2000)当前20页，总共98页。primarydopaminedeficiencyD2receptorblockadesecondarydopaminedeficiencymesocorticalpathwayincreaseinnegativesymptoms10-11StahlSM,EssentialPsychopharmacology(2000)当前21页，总共98页。nigrostriatalpathway当前22页，总共98页。tuberoinfundibularpathway当前23页，总共98页。positivesymptomspsychoticdepressionbipolarchildhoodpsychoticillnessesschizo-affectiveAlzheimer’s10-2StahlSM,EssentialPsychopharmacology(2000)当前24页，总共98页。精神分裂症的治疗机制经典抗精神病药物－纯D2受体阻断剂SDA－DA2/5TH2受体阻断剂多受体机制药物DA稳定剂当前25页，总共98页。D2pureD2blocker11-1经典抗精神病药物当前26页，总共98页。pureD2blocker11-2StahlSM,EssentialPsychopharmacology(2000)当前27页，总共98页。Increaseinnegativesymptoms11-3StahlSM,EssentialPsychopharmacology(2000)Mesocorticalpathway当前28页，总共98页。EPSs11-4StahlSM,EssentialPsychopharmacology(2000)Nigrostriatalpathway当前29页，总共98页。Blockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup-regulateThisup-regulationmayleadtotardivedyskinesia11-5StahlSM,EssentialPsychopharmacology(2000)当前30页，总共98页。Prolactinlevelsrise11-6StahlSM,EssentialPsychopharmacology(2000)Tuberoinfundibularpathway当前31页，总共98页。H1M1D21conventionalantipsychoticdrug11-7StahlSM,EssentialPsychopharmacology(2000)当前32页，总共98页。constipationLAXATIVEblurredvisiondrymouthdrowsiness11-8StahlSM,EssentialPsychopharmacology(2000)M1INSERTED当前33页，总共98页。=acetylcholine=dopamine11-9StahlSM,EssentialPsychopharmacology(2000)当前34页，总共98页。=D2blocker11-10StahlSM,EssentialPsychopharmacology(2000)当前35页，总共98页。=anticholinergic11-11StahlSM,EssentialPsychopharmacology(2000)当前36页，总共98页。H1INSERTED11-12StahlSM,EssentialPsychopharmacology(2000)drowsinessweightgain当前37页，总共98页。drowsinessdecreasedbloodpressuredizziness11-13StahlSM,EssentialPsychopharmacology(2000)1INSERTED当前38页，总共98页。1D2haloperidol11-15当前39页，总共98页。5HT2AD2SDA11-16SDA当前40页，总共98页。5HT7125HT2AD2risperidone11-39StahlSM,EssentialPsychopharmacology(2000)当前41页，总共98页。5HT-DAInteractions11-17StahlSM,EssentialPsychopharmacology(2000)Substantianigraraphenucleusbrakebrake当前42页，总共98页。conventionalantipsychoticcaudatenucleus11-25StahlSM,EssentialPsychopharmacology(2000)当前43页，总共98页。serotonin-dopamineantagonistcaudatenucleus11-26StahlSM,EssentialPsychopharmacology(2000)当前44页，总共98页。conventionalantipsychoticCortex11-28StahlSM,EssentialPsychopharmacology(2000)当前45页，总共98页。serotonin-dopamineantagonistCortex11-29StahlSM,EssentialPsychopharmacology(2000)当前46页，总共98页。5HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine11-37多受体机制药物当前47页，总共98页。5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine11-40StahlSM,EssentialPsychopharmacology(2000)当前48页，总共98页。5HT75HT6H1125HT2AD2quetiapine11-41StahlSM,EssentialPsychopharmacology(2000)当前49页，总共98页。AreAntipsychoticswithMultipleTherapeuticMechanismsBetterthanSelectiveDopamine2Antagonists?11-35StahlSM,EssentialPsychopharmacology(2000)multiplemechanisms=sideeffectschlorpromazinesingleselectivemechanisms=lossofsideeffectsHaloperidolmultipletherapeuticmechanisms=improvedefficacyclozapineSDArisperidonequetiapineolanzapine当前50页，总共98页。DA部分激动剂或DA稳定剂

当前51页，总共98页。hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)当前52页，总共98页。精神分裂症的多巴胺假说

高多巴胺通路低多巴胺通路

阳性症状阴性症状当前53页，总共98页。多巴胺部分激动的原理对于多巴胺功能失调理想的治疗

-降低中脑边缘通路的多巴胺活性

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增强中脑皮质通路的多巴胺活性

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不影响结节漏斗部通路和黑质纹状体通路当前54页，总共98页。agonistanxiolyticsedativehypnoticmusclerelaxantanticonvulsantamnesticdependencypartialagonistanxiolyticonlyantagonistnoclinicaleffectpartialinverseagonistpromnestic(memoryenhancing)anxiogenicinverseagonistpromnesticanxiogenicpro-convulsant8-25StahlSM,EssentialPsychopharmacology(2000)当前55页，总共98页。FULLAGONIST--lightisatitsbrightest3-15StahlSM,EssentialPsychopharmacology(2000)当前56页，总共98页。PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)当前57页，总共98页。NOAGONIST--lightisoff3-17StahlSM,EssentialPsychopharmacology(2000)当前58页，总共98页。PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)当前59页，总共98页。神经退行性变凋亡和坏死当前60页，总共98页。“pruning”outofcontrolAdiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”4-22DA过度传递引起细胞凋亡当前61页，总共98页。神经退行性变－－细胞死亡GABA神经元发育不足，谷氨酸神经元过渡释放先天因素和后天因素导致免疫过度激活神经过度兴奋的毒性作用钙离子大量内流自由基大量生成细胞死亡当前62页，总共98页。abnormalgeneproduct10-18StahlSM,EssentialPsychopharmacology(2000)当前63页，总共98页。overexcitationduetoglutamate10-27StahlSM,EssentialPsychopharmacology(2000)当前64页，总共98页。excesscalciumactivatesenzyme10-28StahlSM,EssentialPsychopharmacology(2000)当前65页，总共98页。enzymeproducesfreeradicaltheendisnear10-29StahlSM,EssentialPsychopharmacology(2000)当前66页，总共98页。freeradicalsbegindestroyingthecell10-30StahlSM,EssentialPsychopharmacology(2000)当前67页，总共98页。finally,freeradicalsdestroythecell10-31StahlSM,EssentialPsychopharmacology(2000)当前68页，总共98页。10-20StahlSM,EssentialPsychopharmacology(2000)apoptosis/necrosis100%50%015204060当前69页，总共98页。精神分裂症治疗药物治疗，主要改变传递异常，不能改变发育异常和阻断退行性变针对退行性变的非抗精神病药物治疗免疫调节剂自由基俘获剂或清除剂非药物治疗当前70页，总共98页。免疫异常和免疫调节剂治疗既往研究发现精神分裂症免疫过度激活当前71页，总共98页。Decreasedproductionofinterleukin-2(IL-2),IL-2secretingcellsandCD4+cellsinmedication-freepatientswithschizophrenia

(Zhang,Zhouetal,JournalofPsychiatricResearch2002)研究发现精神分裂症患者存在IL-2产物生成降低，与T细胞数目减少，IL-2分泌减少有关当前72页，总共98页。

Elevatedinterleukin-2,interleukin-6andinterleukin-8serumlevelsinneuroleptic-freeschizophrenia:associationwithpsychopathology(Zhang,Zhouetal,SchizophreniaResearch2002)研究进一步发现未服抗精神病药物的不同亚型精神分裂症患者细胞因子改变不同当前73页，总共98页。Changesinseruminterleukin-2,-6,and-8levelsbeforeandduringtreatmentwithrisperidoneandhaloperidol:relationshiptooutcomeinschizophrenia(Zhang,Zhouetal,JournalofClinicalPsychiatry2004)典型和非典型抗精神病药物均部分改善精神分裂症患者的细胞因子异常，且基线的细胞因子水平可预测药物疗效当前74页，总共98页。CortisolandCytokinesinChronicandTreatment-ResistantPatientswithSchizophrenia:AssociationwithPsychopathologyandResponsetoAntipsychotics(Zhang,Zhouetal,Neuropsychopharmacology2005)未服抗精神病药物的患者细胞因子的改变与其HPA轴功能紊乱相关，且经过药物治疗改善后这些改变趋于正常，提示这些改变是症状相关的当前75页，总共98页。Tumournecrosisfactoralphapolymorphism(-1031T/C)isassociatedwithageofonsetofschizophrenia.(Zhangetal,MolecularPsychiatry2005)肿瘤坏死因子－alpha基因11031T/C多态性与早发型精神分裂症有关当前76页，总共98页。其他相关论文当前77页，总共98页。当前78页，总共98页。免疫调节剂治疗精神分裂症的研究接受利培酮治疗的首发精神分裂症celecoxib增效作用的双盲对照研究Adouble-blind,Placebo-controlledtrialofcelecoxibaddedtorisperidoneintreatment-naïve,Firstepisodepatientswithschizophrenia(Grant:03T-459)，2003～2006;青蒿素对精神分裂症的增效作用研究Adouble-blind,placebo-controlledtrialofartemisininaddedtorisperidoneintreatment-naïve,firstepisodepatientswithschizophrenia(Grant#:05T-726)，2006～2009.当前79页，总共98页。当前80页，总共98页。当前81页，总共98页。当前82页，总共98页。当前83页，总共98页。当前84页，总共98页。当前85页，总共98页。当前86页，总共98页。当前87页，总共98页。当前88页，总共98页。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）当前89页，总共98页。5、谭云龙，周东丰，张向阳等．迟发性运动障碍患者血浆超氧化物歧化酶、过氧化化氢酶、谷胱苷肽过氧化物酶活性及丙二醛水平的改变．中华精神科杂志，2005，38（3）：166－168．

6、谭云龙，周东丰，邹义壮等．迟发性运动障碍患者血清泌乳素浓度分析．中国心理卫生杂志，2005,19（7）：463－466．7、谭云龙，周东丰，邹义壮．维生素E对迟发性运动障碍模型大鼠的影响．中华精神科杂志，2004，37（3）：1