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1、精神疾病的神经生物学基精神疾病的神经生物学基础及精神病药物作用机理础及精神病药物作用机理abnormal geneINHERITED DISEASE100% will develop the inherited disease (classical autosomal dominant pattern)4-1Stahl S M, Essential Psychopharmacology (2000)abnormal gene productRISK FACTOR 1an enzyme is too slow ever since birth so it is hard to metaboliz
2、e neurotransmitters when release is very fastRISK FACTOR 2some neurons migrated too far during development in uteroRISK FACTOR 3some of the wrong synapses were eliminated in adolescenceRISK FACTOR 4nerves fire too fast when you see your mother1-3 are inherited genetic “hits” - 4 & 5 are environmenta
3、l “hits” expressed through abnormal genetic responsesRISK FACTOR 5nerves fire too fast when you take “speed”4-2Stahl S M, Essential Psychopharmacology (2000)LIFE EVENTSFILTERpersonality/coping skillsgenetic vulnerability factors for depression4-3Stahl S M, Essential Psychopharmacology (2000)even if
4、you inherit the gene for Schizophrenia, the chances of whether or not you develop the disease may be affected by outside factorsbad childhooddivorcevirus or toxinschizophrenia4-4Stahl S M, Essential Psychopharmacology (2000)MINOR STRESSORS(DNA with predisposition for schizophrenia - highly biologica
5、lly determined)SCHIZOPHRENIAMODERATE STRESSORS(DNA with predisposition for depression - moderately biologically determined)DEPRESSIONMAJOR STRESSORS(“normal” DNA)PTSD4-5Stahl S M, Essential Psychopharmacology (2000)good neuronal selection= healthy neuron= defective neuronbad neuronal selection4-6Sta
6、hl S M, Essential Psychopharmacology (2000)bad migrationgood migration4-7Stahl S M, Essential Psychopharmacology (2000)CORRECT WIRING4-8Stahl S M, Essential Psychopharmacology (2000)WRONG WIRING4-9Stahl S M, Essential Psychopharmacology (2000)normal developmentadult degenerative disease4-10Stahl S M
7、, Essential Psychopharmacology (2000)undeveloped neurondevelopmental disease or no stimulation4-11Stahl S M, Essential Psychopharmacology (2000)growth factor (protein)4-12Stahl S M, Essential Psychopharmacology (2000)growth factor (protein)4-13Stahl S M, Essential Psychopharmacology (2000)New neuron
8、 is implanted to take over the functions of the dead neuron4-14Stahl S M, Essential Psychopharmacology (2000)= calciumCalcium entering neuron at a normal rateCalcium entering neuron too quickly4-16glutamate opens ion channel, allowing calcium to enter the cell.4-18Stahl S M, Essential Psychopharmaco
9、logy (2000)too much neurotrans-mission.can lead to panic attacks4-19Stahl S M, Essential Psychopharmacology (2000)4-20Stahl S M, Essential Psychopharmacology (2000)too much neurotrans-mission.can lead to dendritic death4-21Stahl S M, Essential Psychopharmacology (2000)“pruning” out of controlA disea
10、se may let the normal process of pruning get out of control. The disease can cause the neuron to be “pruned to death.”4-22Stahl S M, Essential Psychopharmacology (2000)even more neurotrans-mission.can lead to cell death4-23Stahl S M, Essential Psychopharmacology (2000)4-24Stahl S M, Essential Psycho
11、pharmacology (2000)new neurotransmitter is given a as drug to take over the functions of the dead neuron4-25Stahl S M, Essential Psychopharmacology (2000)Finally, the neuron is destroyed by the excess calcium4-17Stahl S M, Essential Psychopharmacology (2000)精神分裂症及相关精神疾病n n精神分裂症精神分裂症n n物质滥用导致的精神障碍物质滥
12、用导致的精神障碍n n精神分裂症样障碍精神分裂症样障碍n n分裂情感障碍分裂情感障碍n n妄想性障碍妄想性障碍n n短暂精神障碍短暂精神障碍n n共患精神障碍共患精神障碍n n躯体疾病引起的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n n躁狂症n n抑郁症n n认知障碍n nAlzheimer病精神分裂症的五维症状n n阳性症状n n阴性症状n n攻击敌意n n认知改变n n情感改变阳性症状n n妄想n n幻觉n n社交中的夸大言语n n语言解体（破裂）n n行为解体n n激越阴性症状n n情感迟钝情感迟钝n n情感退缩情感退缩n n人际关系恶劣人际关系恶劣n n被动性
13、被动性n n社会性退缩社会性退缩n n抽象思维障碍抽象思维障碍n n自主性缺乏自主性缺乏n n刻板思维刻板思维n n语言和思想的量和流畅性降低语言和思想的量和流畅性降低n n快感缺失快感缺失n n注意力损害注意力损害n n有目的行为受损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n n暴力n n自伤、自杀n n其他形式的伤害情感症状抑郁和焦虑n n抑郁情感n n焦虑情绪n n罪恶感n n紧张n n忧虑n n坐立不安认知症状n n思维异常n n语言怪异、不连贯、语词新作n n注意缺损、信息加工过程受损n n学校能力受损n n执行功能受损schizophreniapositive
14、symptomsnegative symptomsanx/depaggressive symptomscognitive symptoms10-1Stahl S M, Essential Psychopharmacology (2000)positive symptomspsychotic depressionbipolarchildhood psychotic illnessesschizo- affectiveAlzheimers10-2Stahl S M, Essential Psychopharmacology (2000)negative symptoms1 deficit2 to
15、environmental deprivation2 to positive symptoms2 to EPS2 to depression10-3Stahl S M, Essential Psychopharmacology (2000)schizophreniaAlzheimersautismpost stroke10-4Stahl S M, Essential Psychopharmacology (2000)cognitive symptomsbipolarADHD/ conduct disorderborderline personality disorderchildhood ps
16、ychosisschizophreniaAlzheimer & dementias10-5Stahl S M, Essential Psychopharmacology (2000)aggressive symptomsbipolartreatment resistantpsychotic depressionorganicmajor depressionchildschizophrenia/ schizoaffective10-6Stahl S M, Essential Psychopharmacology (2000)depressionhypothalamusdcNucleus accu
17、mbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M, Essential Psychopharmacology (2000)mesolimbic pathway10-8Stahl S M, Essential Psychopharmacology (2000)mesolimbic overactivity = positive symptoms of psychosis10-9Stahl S M, Essential Psychopharmacology (2000)meso-cortical
18、pathway10-10Stahl S M, Essential Psychopharmacology (2000)primary dopamine deficiencyD2 receptor blockadesecondary dopamine deficiencymesocortical pathwayincrease in negative symptoms10-11Stahl S M, Essential Psychopharmacology (2000)nigrostriatal pathwaytubero infundibular pathwaypoorly innervatedt
19、oxic or genetic insultdysfunctiondeathpoor neuronal migrationinadequate synapse selectionnormal DNAnormal DNAabnormal DNAabnormal DNAabnormal gene for schizophrenia10-17Stahl S M, Essential Psychopharmacology (2000)abnormal gene product10-18Stahl S M, Essential Psychopharmacology (2000)10-20Stahl S
20、M, Essential Psychopharmacology (2000)apoptosis/ necrosis100% 50% 015204060GLU (Glutamate)GlutamineGLUTAMATE IS PRODUCEDGlutaminaseGlutamateGlutamateGlutamate synthetaseGlutamineGlial cell10-21Stahl S M, Essential Psychopharmacology (2000)GLUTAMATE IS REMOVED10-22Stahl S M, Essential Psychopharmacol
21、ogy (2000)GLUTAMATE RECEPTORSNMDA receptorAMPA receptorkainate receptormetabotropic receptor10-23Stahl S M, Essential Psychopharmacology (2000)glycine sitezinc sitepolyamine siteMg site (in the ion channel)PCP site (in the ion channel)10-24Stahl S M, Essential Psychopharmacology (2000)normal excitat
22、ory neurotransmission10-25Stahl S M, Essential Psychopharmacology (2000)SPECTRUM OF EXCITATION BY GLUTAMATE10-26Stahl S M, Essential Psychopharmacology (2000)Excess excitation- Mania- PanicExcitotoxicity- Damage to neuronsExcitotoxicity- Slow neuro- degenerationExcitotoxicity- Catastrophic neurodege
23、nerationNormal excitationover excitation due to glutamate10-27Stahl S M, Essential Psychopharmacology (2000)excess calcium activates enzyme10-28Stahl S M, Essential Psychopharmacology (2000)enzyme produces free radicalthe end is near10-29Stahl S M, Essential Psychopharmacology (2000)enzyme produces
24、free radicalthe end is near10-29Stahl S M, Essential Psychopharmacology (2000)free radicals begin destroying the cell10-30Stahl S M, Essential Psychopharmacology (2000)finally, free radicals destroy the cell10-31Stahl S M, Essential Psychopharmacology (2000)neuroprotectionglutamate antagonist blocks
25、 excitotoxic neurotransmissionglutamate antagonist10-32Stahl S M, Essential Psychopharmacology (2000)free radical scavenger10-33Stahl S M, Essential Psychopharmacology (2000)Dead Neuron or Loss of Dendrites10-34Stahl S M, Essential Psychopharmacology (2000)Genetic Programming of ApoptosisPrenatal An
26、oxia / Infection / ToxinsPositive Symptoms Causing Excitoxicity抗精神病药物治疗机制n n经典抗精神病药物纯D2受体阻断剂n nSDADA2/5TH2受体阻断剂n n多受体机制药物n nDA稳定剂D2pure D2 blocker11-1经典抗精神病药物经典抗精神病药物pure D2 blocker11-2Stahl S M, Essential Psychopharmacology (2000)Increase in negative symptoms11-3Stahl S M, Essential Psychopharmacol
27、ogy (2000)Mesocortical pathwayEPSs11-4Stahl S M, Essential Psychopharmacology (2000)Nigrostriatal pathwayBlockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulateThis up-regulation may lead to tardive dyskinesia11-5Stahl S M, Essential Psychopharmacology (2000)Prolactin
28、levels rise11-6Stahl S M, Essential Psychopharmacology (2000)Tuberoinfundibular pathwayH1M1D21conventional antipsychotic drug11-7Stahl S M, Essential Psychopharmacology (2000)constipationLAXATIVEblurred visiondry mouthdrowsiness11-8Stahl S M, Essential Psychopharmacology (2000)M1 INSERTED= acetylcho
29、line= dopamine11-9Stahl S M, Essential Psychopharmacology (2000)= D2 blocker11-10Stahl S M, Essential Psychopharmacology (2000)= anticholinergic11-11Stahl S M, Essential Psychopharmacology (2000)H1 INSERTED11-12Stahl S M, Essential Psychopharmacology (2000)drowsinessweight gaindrowsinessdecreased bl
30、ood pressuredizziness11-13Stahl S M, Essential Psychopharmacology (2000)1 INSERTED1D2haloperidol11-155HT2AD2SDA11-16SDA5HT7125HT2AD2risperidone 11-39Stahl S M, Essential Psychopharmacology (2000)5HT-DA Interactions11-17Stahl S M, Essential Psychopharmacology (2000)Substantia nigraraphe nucleusbrakeb
31、rakeserotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor11-18Stahl S M, Essential Psychopharmacology (2000)serotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor11-19Stahl S M, Essential Psychopharmacology (2000)
32、DA neuron5HT neuronpostsynaptic neurondopamineD2 receptor5HT2A receptorNigrostriatal pathway11-21Stahl S M, Essential Psychopharmacology (2000)serotoninNigrostriatal pathwayno dopamine release11-22Stahl S M, Essential Psychopharmacology (2000)SDAD2 receptor11-23Stahl S M, Essential Psychopharmacolog
33、y (2000)Nigrostriatal pathway5HT2A receptorNigrostriatal pathway11-24Stahl S M, Essential Psychopharmacology (2000)conventional antipsychoticcaudate nucleus11-25Stahl S M, Essential Psychopharmacology (2000)serotonin-dopamine antagonistcaudate nucleus11-26Stahl S M, Essential Psychopharmacology (200
34、0)mesocortical pathwayprimary dopamine deficiencysecondary dopamine deficiencydopamine releaseserotoninSDA11-27Stahl S M, Essential Psychopharmacology (2000)conventional antipsychoticCortex11-28Stahl S M, Essential Psychopharmacology (2000)serotonin-dopamine antagonistCortex11-29Stahl S M, Essential
35、 Psychopharmacology (2000)5HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine 11-37多受体机制药物多受体机制药物5HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine 11-40Stahl S M, Essential Psychopharmacology (2000)5HT75HT6H1125HT2AD2quetiapine 11-41Stahl S M, Essential Psychopharmacology (2000)Are Antipsychotics with Multip
36、le Therapeutic Mechanisms Better than Selective Dopamine 2 Antagonists?11-35Stahl S M, Essential Psychopharmacology (2000)multiple mechanisms = side effectschlorpromazinesingle selective mechanisms = loss of side effectsHaloperidolmultiple therapeutic mechanisms = improved efficacyclozapineSDArisper
37、idonequetiapineolanzapineDA部分激动剂或DA稳定剂hypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M, Essential Psychopharmacology (2000)精神分裂症的多巴胺假说 高多巴胺通路高多巴胺通路 低多巴胺通路低多巴胺通路 阳性症状阳性症状 阴性症状阴性症状多巴胺胺部分激动的原理n n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 -
38、- 不影响结节漏斗部通路和黑质纹状体通路agonistanxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependencypartial agonistanxiolytic onlyantagonistno clinical effectpartial inverse agonistpromnestic (memory enhancing) anxiogenicinverse agonistpromnesticanxiogenic pro-convulsant8-25Stahl S M, Essential Psy
39、chopharmacology (2000)FULL AGONIST - light is at its brightest3-15Stahl S M, Essential Psychopharmacology (2000)PARTIAL AGONIST - light is dimmed but still shining3-16Stahl S M, Essential Psychopharmacology (2000)NO AGONIST - light is off3-17Stahl S M, Essential Psychopharmacology (2000)PARTIAL AGON
40、IST - light is dimmed but still shining3-16Stahl S M, Essential Psychopharmacology (2000)精神分裂症治疗目标n n纠正中枢神经递质功能紊乱n n减缓兴奋毒性作用引起的神经元损害n n减缓神经退行性变过程n n消除5维症状n n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n n各种类型发作都应首选情感稳定剂n n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n n谨慎使用抗抑郁药n n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
41、剂碳酸鋰1、 为双相障碍首选药物，n n 适应症为躁狂发作、混合发作、n n 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：n n口干、便秘、腹泻、恶心n n多饮、多尿n n震颤、发力、嗜睡、视力模糊、反射亢进n n白细胞升高n n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n n通常日量10002000mg，分次服n n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/Ln n老年人酌减经典情感稳定剂碳酸鋰与其他药物相互作用n n减低其他药物浓度和作用n n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
42、症：n n躁狂发作n n快速循环n n预防双相障碍复发2、丙戊酸纳和丙戊酸镁 不良反应n n恶心、呕吐、腹泻食欲下降n n嗜睡、乏力、震颤、共济失调、兴奋、躁动、严重时意识模糊或昏迷n n血小板减少或凝血异常、白细胞减少n n皮疹2、丙戊酸纳和丙戊酸镁 常用剂量n n300400mg 每日3次，缓慢加量，总量不超过1800mg/日n n白细胞减少及严重肝损害者禁用，肝肾功能不全者减量n n定期查肝功血象n n老年人酌减2、丙戊酸纳和丙戊酸镁 与其他药物相互作用n n可导致其他药物血浓度下降或药效减低n n不宜与氯硝西泮合用n n阿司匹林增加其毒性n n多种抗精神病药物，TCA、MAOI等减低其
43、效应其他情感稳定剂n n卡马西平n n托吡酯n n拉莫三嗪情感稳定剂的增效剂n n甲状腺素：T3，T4n n钙离子通道阻断剂异博定、尼莫地平n n5HT1A受体拮抗剂丁螺环酮双相情感障碍抑郁发作的治疗n n情感稳定剂：碳酸鋰、丙戊酸纳、卡马西平等n n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单胺氧化酶抑制剂三环类抗抑郁药SNRIsn n非典型抗精神病药物要注意的问题n n尽量选择不容易诱发躁狂的抗抑郁药n n抗抑郁药物使用时间尽量短，症状消失即可停药，不应当用抗抑郁药进行长期维持治疗；n n应全程使用情感稳定剂，而不仅是在维持期治疗；n n疗效不好或起效慢可以合并非典型抗精神病药物躁狂发作或双相障碍治疗中应注意问题n n首选情感稳定剂，一种或数种合并n n必要时合并非经典抗精神病药物，尽量不用经典药物n n症状缓解继续后原治疗23月n n转入维持期应缓慢减量双相障碍快速循环治疗应注意的问题n n首选情感稳定剂，可以单独或合并n n不应使用抗抑郁药n n积极选择非经典抗精神病药物n n必要时合并ECTn n缓解后维持期应更长
