精神分裂症病理机制的研究进展

精神分裂症病理机制的研究进展和治疗学发展北京大学精神卫生研究所周东丰基本病理机制神经发育异常神经传递异常神经退行性变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)发育异常的表现选择异常迁移异常突触连接异常goodneuronalselection=healthyneuron=defectiveneuronbadneuronalselection4-6选择异常badmigrationgoodmigration4-7迁移异常normalDNAnormalDNA正确连线abnormalDNAabnormalDNA错误连线4-9StahlSM,Essentialsychopharmacology(2000)神经传递异常的表现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D2pureD2blocker11-1经典抗精神病药物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多受体机制药物5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine11-40StahlSM,EssentialPsychopharmacology(2000)5HT75HT6H1125HT2AD2quetiapine11-41StahlSM,EssentialPsychopharmacology(2000)AreAntipsychoticswithMultipleTherapeuticMechanismsBetterthanSelectiveDopamine2Antagonists?11-35StahlSM,EssentialPsychopharmacology(2000)multiplemechanisms=sideeffectschlorpromazinesingleselectivemechanisms=lossofsideeffectsHaloperidolmultipletherapeuticmechanisms=improvedefficacyclozapineSDArisperidonequetiapineolanzapineDA部分激动剂或DA稳定剂

hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)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

-增强中脑皮质通路的多巴胺活性

-不影响结节漏斗部通路和黑质纹状体通路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)神经退行性变凋亡和坏死“pruning”outofcontrolAdiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”4-22DA过度传递引起细胞凋亡神经退行性变－－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

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其他相关论文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)，2006～2009.1、YLTan,DFZhou,XYZhang.Decreasedplasmabrain-derivedneurotrophicfactorlevelsinschizophrenicpatientswithtardivedyskinesia:associationwithdyskineticmovements.SchizophreniaResearch,2005,74(2-3):176-183.（IF=4.072，2003）2、YLTan,DFZhou,LYCao,YZZou,XYZhang.DecreasedBDNFinserumofpatientswithchronicschizophren