精神疾病的神经生物学基础.ppt

精神疾病的神经生物学基础及精神病药物作用机理,1-3 are inherited genetic “hits” - 4 & 5 are environmental “hits” expressed through abnormal genetic responses,LIFE EVENTS,FILTER,personality/coping skills,genetic vulnerability factors for depression,CORRECT WIRING,WRONG WIRING,growth factor (protein),growth factor (protein),New neuron is implanted to take over the functions of the dead neuron,= calcium,Calcium entering neuron at a normal rate,Calcium entering neuron too quickly,4-16,glutamate opens ion channel, allowing calcium to enter the cell.,too much neurotrans-mission.,can lead to panic attacks,too much neurotrans-mission.,can lead to dendritic death,“pruning” out of control,A disease may let the normal process of pruning get out of control. The disease can cause the neuron to be “pruned to death.”,even more neurotrans-mission.,can lead to cell death,new neurotransmitter is given a as drug to take over the functions of the dead neuron,Finally, the neuron is destroyed by the excess calcium,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,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,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,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,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,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,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,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,schizophrenia,positive symptoms,negative symptoms,cognitive symptoms,aggressive symptoms,depression,c,DOPAMINE PATHWAYS,mesolimbic pathway,mesolimbic overactivity = positive symptoms of psychosis,meso-cortical pathway,primary dopamine deficiency,D2 receptor blockade,secondary dopamine deficiency,mesocortical pathway,increase in negative symptoms,nigrostriatal pathway,tubero infundibular pathway,poorly innervated,poor neuronal migration,inadequate synapse selection,normal DNA,normal DNA,abnormal DNA,abnormal DNA,abnormal gene for schizophrenia,abnormal gene product,apoptosis/ necrosis,100%,50%,0,15,20,40,60,GLU (Glutamate),Glutamine,GLUTAMATE IS PRODUCED,Glutaminase,Glutamate,Glutamate,Glutamate synthetase,Glutamine,Glial cell,GLUTAMATE IS REMOVED,GLUTAMATE RECEPTORS,NMDA receptor,AMPA receptor,kainate receptor,metabotropic receptor,glycine site,zinc site,polyamine site,Mg site (in the ion channel),PCP site (in the ion channel),normal excitatory neurotransmission,SPECTRUM OF EXCITATION BY GLUTAMATE,Excess excitation - Mania - Panic,Excitotoxicity - Damage to neurons,Excitotoxicity - Slow neuro- degeneration,Excitotoxicity - Catastrophic neurodegeneration,Normal excitation,over excitation due to glutamate,excess calcium activates enzyme,enzyme produces free radical,the end is near,enzyme produces free radical,the end is near,free radicals begin destroying the cell,finally, free radicals destroy the cell,free radical scavenger,Dead Neuron or Loss of Dendrites,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,D2,pure D2 blocker,pure D2 blocker,Mesocortical pathway,Nigrostriatal pathway,Blockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulate,This up-regulation may lead to tardive dyskinesia,Tuberoinfundibular pathway,H1,M1,D2,conventional antipsychotic drug,M1 INSERTED,= acetylcholine,= dopamine,= D2 blocker,= anticholinergic,H1 INSERTED,D2,haloperidol,5HT2A,D2,SDA,5HT7,5HT2A,D2,risperidone,5HT-DA Interactions,serotonin neuron,dopamine neuron,Substantia nigra,Raphe,dopamine,5HT2A receptor,serotonin,5HT2A receptor,serotonin neuron,dopamine neuron,Substantia nigra,Raphe,dopamine,5HT2A receptor,serotonin,5HT2A receptor,DA neuron,5HT neuron,postsynaptic neuron,dopamine,D2 receptor,5HT2A receptor,Nigrostriatal pathway,serotonin,Nigrostriatal pathway,no dopamine release,SDA,D2 receptor,Nigrostriatal pathway,5HT2A receptor,Nigrostriatal pathway,conventional antipsychotic,caudate nucleus,serotonin-dopamine antagonist,caudate nucleus,mesocortical pathway,primary dopamine deficiency,secondary dopamine deficiency,dopamine release,serotonin,SDA,conventional antipsychotic,Cortex,serotonin-dopamine antagonist,Cortex,5HT7,5HT6,5HT3,5HT2C,5HT1A,M1,H1,D1,D3,D4,5HT2A,D2,clozapine,5HT6,5HT3,5HT2C,M1,H1,D1,D3,D4,5HT2A,D2,olanzapine,5HT7,5HT6,H1,5HT2A,D2,quetiapine,Are Antipsychotics with Multiple Therapeutic Mechanisms Better than Selective Dopamine 2 Antagonists?,DA部分激动剂或DA稳定剂,c,DOPAMINE PATHWAYS,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,FULL AGONIST - light is at its brightest,PARTIAL AGONIST - light is dimmed but still shining,NO AGONIST - light is off,PARTIAL AGONIST - light is dimmed but still shining,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,双向情感障碍的治疗,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,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,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,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,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,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,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,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,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,其他情感稳定剂,卡马西平 托吡酯 拉莫三嗪,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,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