精神分裂癥病理機制的研究進(jìn)展演示文稿

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

當(dāng)前51頁，總共98頁。hypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYS10-7StahlSM,EssentialPsychopharmacology(2000)當(dāng)前52頁，總共98頁。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53頁，總共98頁。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54頁，總共98頁。agonistanxiolyticsedativehypnoticmusclerelaxantanticonvulsantamnesticdependencypartialagonistanxiolyticonlyantagonistnoclinicaleffectpartialinverseagonistpromnestic(memoryenhancing)anxiogenicinverseagonistpromnesticanxiogenicpro-convulsant8-25StahlSM,EssentialPsychopharmacology(2000)當(dāng)前55頁，總共98頁。FULLAGONIST--lightisatitsbrightest3-15StahlSM,EssentialPsychopharmacology(2000)當(dāng)前56頁，總共98頁。PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)當(dāng)前57頁，總共98頁。NOAGONIST--lightisoff3-17StahlSM,EssentialPsychopharmacology(2000)當(dāng)前58頁，總共98頁。PARTIALAGONIST--lightisdimmedbutstillshining3-16StahlSM,EssentialPsychopharmacology(2000)當(dāng)前59頁，總共98頁。神經(jīng)退行性變凋亡和壞死當(dāng)前60頁，總共98頁?！皃runing”outofcontrolAdiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”4-22DA過度傳遞引起細(xì)胞凋亡當(dāng)前61頁，總共98頁。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62頁，總共98頁。abnormalgeneproduct10-18StahlSM,EssentialPsychopharmacology(2000)當(dāng)前63頁，總共98頁。overexcitationduetoglutamate10-27StahlSM,EssentialPsychopharmacology(2000)當(dāng)前64頁，總共98頁。excesscalciumactivatesenzyme10-28StahlSM,EssentialPsychopharmacology(2000)當(dāng)前65頁，總共98頁。enzymeproducesfreeradicaltheendisnear10-29StahlSM,EssentialPsychopharmacology(2000)當(dāng)前66頁，總共98頁。freeradicalsbegindestroyingthecell10-30StahlSM,EssentialPsychopharmacology(2000)當(dāng)前67頁，總共98頁。finally,freeradicalsdestroythecell10-31StahlSM,EssentialPsychopharmacology(2000)當(dāng)前68頁，總共98頁。10-20StahlSM,EssentialPsychopharmacology(2000)apoptosis/necrosis100%50%015204060當(dāng)前69頁，總共98頁。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70頁，總共98頁。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71頁，總共98頁。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72頁，總共98頁。

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)胞因子改變不同當(dāng)前73頁，總共98頁。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74頁，總共98頁。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75頁，總共98頁。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76頁，總共98頁。其他相關(guān)論文當(dāng)前77頁，總共98頁。當(dāng)前78頁，總共98頁。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79頁，總共98頁。當(dāng)前80頁，總共98頁。當(dāng)前81頁，總共98頁。當(dāng)前82頁，總共98頁。當(dāng)前83頁，總共98頁。當(dāng)前84頁，總共98頁。當(dāng)前85頁，總共98頁。當(dāng)前86頁，總共98頁。當(dāng)前87頁，總共98頁。當(dāng)前88頁，總共98頁。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89頁，總共98頁。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（3）：1