精神疾病的神经生物学基础ppt课件.ppt

精神疾病的神经生物学基础及精神病药物作用机理,1,.,2,1-3areinheritedgenetic“hits”-4&5areenvironmental“hits”expressedthroughabnormalgeneticresponses,3,LIFEEVENTS,FILTER,personality/copingskills,geneticvulnerabilityfactorsfordepression,4,5,6,7,8,CORRECTWIRING,9,WRONGWIRING,10,11,12,growthfactor(protein),13,growthfactor(protein),14,Newneuronisimplantedtotakeoverthefunctionsofthedeadneuron,15,=calcium,Calciumenteringneuronatanormalrate,16,Calciumenteringneurontooquickly,4-16,17,glutamateopensionchannel,allowingcalciumtoenterthecell.,18,toomuchneurotrans-mission.,canleadtopanicattacks,19,20,toomuchneurotrans-mission.,canleadtodendriticdeath,21,“pruning”outofcontrol,Adiseasemayletthenormalprocessofpruninggetoutofcontrol.Thediseasecancausetheneurontobe“prunedtodeath.”,22,evenmoreneurotrans-mission.,canleadtocelldeath,23,24,newneurotransmitterisgivenaasdrugtotakeoverthefunctionsofthedeadneuron,25,Finally,theneuronisdestroyedbytheexcesscalcium,26,精神分裂症及相关精神疾病,精神分裂症物质滥用导致的精神障碍精神分裂症样障碍分裂情感障碍妄想性障碍短暂精神障碍共患精神障碍躯体疾病引起的精神障碍,27,经常合并精神疾病特征性症状的精神障碍,躁狂症抑郁症认知障碍Alzheimer病,28,精神分裂症的五维症状,阳性症状阴性症状攻击敌意认知改变情感改变,29,阳性症状,妄想幻觉社交中的夸大言语语言解体（破裂）行为解体激越,30,阴性症状,情感迟钝情感退缩人际关系恶劣被动性社会性退缩抽象思维障碍自主性缺乏刻板思维语言和思想的量和流畅性降低快感缺失注意力损害有目的行为受损,31,攻击和敌意,可含概于阳性症状内，但特征性地具有暴力自伤、自杀其他形式的伤害,32,情感症状抑郁和焦虑,抑郁情感焦虑情绪罪恶感紧张忧虑坐立不安,33,认知症状,思维异常语言怪异、不连贯、语词新作注意缺损、信息加工过程受损学校能力受损执行功能受损,34,schizophrenia,35,positivesymptoms,36,negativesymptoms,37,cognitivesymptoms,38,aggressivesymptoms,39,depression,40,c,DOPAMINEPATHWAYS,41,mesolimbicpathway,42,mesolimbicoveractivity=positivesymptomsofpsychosis,43,meso-corticalpathway,44,primarydopaminedeficiency,D2receptorblockade,secondarydopaminedeficiency,mesocorticalpathway,increaseinnegativesymptoms,45,nigrostriatalpathway,46,tuberoinfundibularpathway,47,poorlyinnervated,poorneuronalmigration,inadequatesynapseselection,48,normalDNA,normalDNA,49,abnormalDNA,abnormalDNA,50,abnormalgeneforschizophrenia,51,abnormalgeneproduct,52,apoptosis/necrosis,100%,50%,0,15,20,40,60,53,GLU(Glutamate),Glutamine,GLUTAMATEISPRODUCED,Glutaminase,Glutamate,Glutamate,Glutamatesynthetase,Glutamine,Glialcell,54,GLUTAMATEISREMOVED,55,GLUTAMATERECEPTORS,NMDAreceptor,AMPAreceptor,kainatereceptor,metabotropicreceptor,56,glycinesite,zincsite,polyaminesite,Mgsite(intheionchannel),PCPsite(intheionchannel),57,normalexcitatoryneurotransmission,58,SPECTRUMOFEXCITATIONBYGLUTAMATE,Excessexcitation-Mania-Panic,Excitotoxicity-Damagetoneurons,Excitotoxicity-Slowneuro-degeneration,Excitotoxicity-Catastrophicneurodegeneration,Normalexcitation,59,overexcitationduetoglutamate,60,excesscalciumactivatesenzyme,61,enzymeproducesfreeradical,theendisnear,62,enzymeproducesfreeradical,theendisnear,63,freeradicalsbegindestroyingthecell,64,finally,freeradicalsdestroythecell,65,66,freeradicalscavenger,67,DeadNeuronorLossofDendrites,68,抗精神病药物治疗机制,经典抗精神病药物纯D2受体阻断剂SDADA2/5TH2受体阻断剂多受体机制药物DA稳定剂,69,D2,pureD2blocker,70,pureD2blocker,71,Mesocorticalpathway,72,Nigrostriatalpathway,73,Blockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup-regulate,Thisup-regulationmayleadtotardivedyskinesia,74,Tuberoinfundibularpathway,75,H1,M1,D2,conventionalantipsychoticdrug,76,M1INSERTED,77,=acetylcholine,=dopamine,78,=D2blocker,79,=anticholinergic,80,H1INSERTED,81,82,D2,haloperidol,83,5HT2A,D2,SDA,84,5HT7,5HT2A,D2,risperidone,85,5HT-DAInteractions,86,serotoninneuron,dopamineneuron,Substantianigra,Raphe,dopamine,5HT2Areceptor,serotonin,5HT2Areceptor,87,serotoninneuron,dopamineneuron,Substantianigra,Raphe,dopamine,5HT2Areceptor,serotonin,5HT2Areceptor,88,DAneuron,5HTneuron,postsynapticneuron,dopamine,D2receptor,5HT2Areceptor,Nigrostriatalpathway,89,serotonin,Nigrostriatalpathway,nodopaminerelease,90,SDA,D2receptor,Nigrostriatalpathway,91,5HT2Areceptor,Nigrostriatalpathway,92,conventionalantipsychotic,caudatenucleus,93,serotonin-dopamineantagonist,caudatenucleus,94,mesocorticalpathway,primarydopaminedeficiency,secondarydopaminedeficiency,dopaminerelease,serotonin,SDA,95,conventionalantipsychotic,Cortex,96,serotonin-dopamineantagonist,Cortex,97,5HT7,5HT6,5HT3,5HT2C,5HT1A,M1,H1,D1,D3,D4,5HT2A,D2,clozapine,98,5HT6,5HT3,5HT2C,M1,H1,D1,D3,D4,5HT2A,D2,olanzapine,99,5HT7,5HT6,H1,5HT2A,D2,quetiapine,100,AreAntipsychoticswithMultipleTherapeuticMechanismsBetterthanSelectiveDopamine2Antagonists?,101,DA部分激动剂或DA稳定剂,102,c,DOPAMINEPATHWAYS,103,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,104,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,105,106,FULLAGONIST-lightisatitsbrightest,107,PARTIALAGONIST-lightisdimmedbutstillshining,108,NOAGONIST-lightisoff,109,PARTIALAGONIST-lightisdimmedbutstillshining,110,精神分裂症治疗目标,纠正中枢神经递质功能紊乱减缓兴奋毒性作用引起的神经元损害减缓神经退行性变过程消除5维症状早诊断，早治疗，尽量选用不损害神经元的非经典抗精神病药物,111,双向情感障碍的治疗,112,.,双相情感障碍药物治疗原则,各种类型发作都应首选情感稳定剂较多采用合并治疗，注意药物相互作注意情感稳定剂药物使用的安全性谨慎使用抗抑郁药必要时选择非经典抗精神病药物,113,情感稳定剂简介经典情感稳定剂碳酸鋰,1、为双相障碍首选药物，适应症为躁狂发作、混合发作、快速循环并可预防躁狂和抑郁发作,114,经典情感稳定剂碳酸鋰,2、不良反应：口干、便秘、腹泻、恶心多饮、多尿震颤、发力、嗜睡、视力模糊、反射亢进白细胞升高肾功能不全、严重心脏疾病禁用,115,经典情感稳定剂碳酸鋰,常用剂量通常日量10002000mg，分次服缓慢加量，监测血锂调整药量，急性期血锂浓度0.61.2mmol/L，维持期0.40.8mmol/L老年人酌减,116,经典情感稳定剂碳酸鋰,与其他药物相互作用减低其他药物浓度和作用吡罗西康可使血锂升高导致锂中毒,117,2、丙戊酸纳和丙戊酸镁,适应症：躁狂发作快速循环预防双相障碍复发,118,2、丙戊酸纳和丙戊酸镁,不良反应恶心、呕吐、腹泻食欲下降嗜睡、乏力、震颤、共济失调、兴奋、躁动、严重时意识模糊或昏迷血小板减少或凝血异常、白细胞减少皮疹,119,2、丙戊酸纳和丙戊酸镁,常用剂量300400mg每日3次，缓慢加量，总量不超过1800mg/日白细胞减少及严重肝损害者禁用，肝肾功能不全者减量定期查肝功血象老年人酌减,120,2、丙戊酸纳和丙戊酸镁,与其他药物相互作用可导致其他药物血浓度下降或药效减低不宜与氯硝西泮合用阿司匹林增加其毒性多种抗精神病药物，TCA、MAOI等减低其效应,121,其他情感稳定剂,卡马西平托吡酯拉莫三嗪,122,情感稳定剂的增效剂,甲状腺素：T3，T4钙离子通道阻断剂异博定、尼莫地平5HT1A受体拮抗剂丁螺环酮,123,双相情感障碍抑郁发作的治疗,情感稳定剂：碳酸鋰、丙戊酸纳、卡马西平等抗抑郁药：首选诱发躁狂少的药物如SSRIs,不应当用单胺氧化酶抑制剂三环类抗抑郁药