精神分裂症病理机制研究进展课件

精神分裂症病理机制的研究进精神分裂症病理机制的研究进展和治疗学发展展和治疗学发展精神分裂症病理机制的研究进展和治疗学发展1基本病理机制基本病理机制n n神经发育异常n n神经传递异常n n神经退行性变基本病理机制神经发育异常2有关发育异常有关发育异常n n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有关发育异常遗传和环境相互作用3abnormal geneINHERITED DISEASE100%will develop the inherited disease(classical autosomal dominant pattern)4-1Stahl S M,Essential Psychopharmacology(2000)abnormal gene productabnormal geneINHERITED DISEASE4RISK FACTOR 1an enzyme is too slow ever since birth so it is hard to metabolize 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 environmental“hits”expressed through abnormal genetic responsesRISK FACTOR 5nerves fire too fast when you take“speed”4-2Stahl S M,Essential Psychopharmacology(2000)RISK FACTOR 1RISK FACTOR 2RISK5LIFE EVENTSFILTERpersonality/coping skillsgenetic vulnerability factors for depression4-3Stahl S M,Essential Psychopharmacology(2000)LIFE EVENTSFILTERpersonality/c6even if 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)even if you inherit the gene f7MINOR STRESSORS(DNA with predisposition for schizophrenia-highly biologically determined)SCHIZOPHRENIAMODERATE STRESSORS(DNA with predisposition for depression-moderately biologically determined)DEPRESSIONMAJOR STRESSORS(“normal”DNA)PTSD4-5Stahl S M,Essential Psychopharmacology(2000)MINOR STRESSORS(DNA with predi8发育异常的表现发育异常的表现n n选择异常n n迁移异常n n突触连接异常发育异常的表现选择异常9good neuronal selection=healthy neuron=defective neuronbad neuronal selection4-6选择异常选择异常good neuronal selection=healt10bad migrationgood migration4-7迁移异常迁移异常bad migrationgood migration4-711normal DNAnormal DNAnormal DNAnormal DNA12正确连线正确连线正确连线13abnormal DNAabnormal DNAabnormal DNAabnormal DNA14错误连线错误连线4-9Stahl S M,Essential sychopharmacology(2000)错误连线4-9Stahl S M,Essential sy15神经传递异常的表现神经传递异常的表现神经传递异常的表现16hypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M,Essential Psychopharmacology(2000)hypothalamusdcNucleus accumben17mesolimbic pathway10-8Stahl S M,Essential Psychopharmacology(2000)mesolimbic pathway10-8Stahl S 18mesolimbic overactivity=positive symptoms of psychosis10-9Stahl S M,Essential Psychopharmacology(2000)mesolimbic overactivity=posi19meso-cortical pathway10-10Stahl S M,Essential Psychopharmacology(2000)meso-cortical pathway10-10Stah20primary dopamine deficiencyD2 receptor blockadesecondary dopamine deficiencymesocortical pathwayincrease in negative symptoms10-11Stahl S M,Essential Psychopharmacology(2000)primary dopamine deficiencyD2 21nigrostriatal pathwaynigrostriatal pathway22tubero infundibular pathwaytubero infundibular pathway23positive symptomspsychotic depressionbipolarchildhood psychotic illnessesschizo-affectiveAlzheimers10-2Stahl S M,Essential Psychopharmacology(2000)positive symptomspsychotic dep24精神分裂症的治疗机制精神分裂症的治疗机制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25D2pure D2 blocker11-1经典抗精神病药物经典抗精神病药物D2pure D2 blocker11-1经典抗精神病药物26pure D2 blocker11-2Stahl S M,Essential Psychopharmacology(2000)pure D2 blocker11-2Stahl S M,27Increase in negative symptoms11-3Stahl S M,Essential Psychopharmacology(2000)Mesocortical pathwayIncrease in negative symptoms128EPSs11-4Stahl S M,Essential Psychopharmacology(2000)Nigrostriatal pathwayEPSs11-4Stahl S M,Essential P29Blockade 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)Blockade of receptors in the n30Prolactin levels rise11-6Stahl S M,Essential Psychopharmacology(2000)Tuberoinfundibular pathwayProlactin levels rise11-6Stahl31H1M1D21conventional antipsychotic drug11-7Stahl S M,Essential Psychopharmacology(2000)H1M1D21conventional antipsycho32constipationLAXATIVEblurred visiondry mouthdrowsiness11-8Stahl S M,Essential Psychopharmacology(2000)M1 INSERTEDconstipationLAXATIVEblurred vi33=acetylcholine=dopamine11-9Stahl S M,Essential Psychopharmacology(2000)=acetylcholine=dopamine11-9S34=D2 blocker11-10Stahl S M,Essential Psychopharmacology(2000)=D2 blocker11-10Stahl S M,Es35=anticholinergic11-11Stahl S M,Essential Psychopharmacology(2000)=anticholinergic11-11Stahl S 36H1 INSERTED11-12Stahl S M,Essential Psychopharmacology(2000)drowsinessweight gainH1 INSERTED11-12Stahl S M,Ess37drowsinessdecreased blood pressuredizziness11-13Stahl S M,Essential Psychopharmacology(2000)1 INSERTEDdrowsinessdecreased blood pres381D2haloperidol11-151D2haloperidol11-15395HT2AD2SDA11-16SDA5HT2AD2SDA11-16SDA405HT7125HT2AD2risperidone 11-39Stahl S M,Essential Psychopharmacology(2000)5HT7125HT2AD2risperidone 11-3415HT-DA Interactions11-17Stahl S M,Essential Psychopharmacology(2000)Substantia nigraraphe nucleusbrakebrake5HT-DA Interactions11-17Stahl 42conventional antipsychoticcaudate nucleus11-25Stahl S M,Essential Psychopharmacology(2000)conventional antipsychoticcaud43serotonin-dopamine antagonistcaudate nucleus11-26Stahl S M,Essential Psychopharmacology(2000)serotonin-dopamine antagonistc44conventional antipsychoticCortex11-28Stahl S M,Essential Psychopharmacology(2000)conventional antipsychoticCort45serotonin-dopamine antagonistCortex11-29Stahl S M,Essential Psychopharmacology(2000)serotonin-dopamine antagonistC465HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine 11-37多受体机制药物多受体机制药物5HT75HT65HT35HT2C5HT1AM1H112D1475HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine 11-40Stahl S M,Essential Psychopharmacology(2000)5HT65HT35HT2CM1H11D1D3D45HT2AD485HT75HT6H1125HT2AD2quetiapine 11-41Stahl S M,Essential Psychopharmacology(2000)5HT75HT6H1125HT2AD2quetiapine 49Are Antipsychotics with Multiple 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 efficacyclozapineSDArisperidonequetiapineolanzapineAre Antipsychotics with Multip50DA部分激动剂或部分激动剂或DA稳定剂稳定剂DA部分激动剂或DA稳定剂51hypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M,Essential Psychopharmacology(2000)hypothalamusdcNucleus accumben52精神分裂症的多巴胺假说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 阴性症状阴性症状精神分裂症的多巴胺假说53多巴多巴胺部分激动的原理部分激动的原理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 -不影响结节漏斗部通路和黑质纹状体通路多巴胺部分激动的原理对于多巴胺功能失调理想的治疗54agonistanxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependencypartial agonistanxiolytic onlyantagonistno clinical effectpartial inverse agonistpromnestic(memory enhancing)anxiogenicinverse agonistpromnesticanxiogenic pro-convulsant8-25Stahl S M,Essential Psychopharmacology(2000)agonistanxiolyticpartial agoni55FULL AGONIST-light is at its brightest3-15Stahl S M,Essential Psychopharmacology(2000)FULL AGONIST-light is at it56PARTIAL AGONIST-light is dimmed but still shining3-16Stahl S M,Essential Psychopharmacology(2000)PARTIAL AGONIST-light is di57NO AGONIST-light is off3-17Stahl S M,Essential Psychopharmacology(2000)NO AGONIST-light is off3-1758PARTIAL AGONIST-light is dimmed but still shining3-16Stahl S M,Essential Psychopharmacology(2000)PARTIAL AGONIST-light is di59神经退行性变神经退行性变n n凋亡和坏死神经退行性变凋亡和坏死60“pruning”out of controlA disease may let the normal process of pruning get out of control.The disease can cause the neuron to be“pruned to death.”4-22DADA过度传递引起细胞凋亡过度传递引起细胞凋亡“pruning”out of controlA dise61神经退行性变细胞死亡神经退行性变细胞死亡n nGABA神经元发育不足，谷氨酸神经元过渡释放n n先天因素和后天因素导致免疫过度激活n n神经过度兴奋的毒性作用n n钙离子大量内流n n自由基大量生成n n细胞死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62abnormal gene product10-18Stahl S M,Essential Psychopharmacology(2000)abnormal gene product10-18Stah63over excitation due to glutamate10-27Stahl S M,Essential Psychopharmacology(2000)over excitation due to glutama64excess calcium activates enzyme10-28Stahl S M,Essential Psychopharmacology(2000)excess calcium activates enzym65enzyme produces free radicalthe end is near10-29Stahl S M,Essential Psychopharmacology(2000)enzyme produces free radicalth66free radicals begin destroying the cell10-30Stahl S M,Essential Psychopharmacology(2000)free radicals begin destroying67finally,free radicals destroy the cell10-31Stahl S M,Essential Psychopharmacology(2000)finally,free radicals destroy6810-20Stahl S M,Essential Psychopharmacology(2000)apoptosis/necrosis100%50%01520406010-20Stahl S M,Essential Psyc69精神分裂症治疗精神分裂症治疗n n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n n针对退行性变的非抗精神病药物治疗n n免疫调节剂n n自由基俘获剂或清除剂n n非药物治疗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70免疫异常和免疫调节剂治疗免疫异常和免疫调节剂治疗n n既往研究发现精神分裂症免疫过度激活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71Decreased production of interleukin-2(IL-2),IL-2 secreting cells and CD4+cells in medication-free patients with schizophrenia(Zhang,Zhou et al,Journal of Psychiatric Research 2002)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分泌减少有关精神分裂症病理机制研究进展课件72Elevated interleukin-2,interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia:association with psychopathology(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者细胞因子改变不同精神分裂症病理机制研究进展课件73Changes in serum interleukin-2,-6,and-8 levels before and during treatment with risperidone and haloperidol:relationship to outcome in schizophrenia(Zhang,Zhou et al,Journal of Clinical Psychiatry 2004)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精神分裂症病理机制研究进展课件74Cortisol and Cytokines in Chronic and Treatment-Resistant Patients with Schizophrenia:Association with Psychopathology and Response to Antipsychotics(Zhang,Zhou et al,Neuropsychopharmacology 2005)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精神分裂症病理机制研究进展课件75Tumour necrosis factor alpha polymorphism(-1031T/C)isassociatedwithageofonsetofschizophrenia.(Zhangetal,MolecularPsychiatry2005)肿瘤坏死因子alpha基因1 1031T/C多态性与早发型精神分裂症有关Tumour necrosis factor alpha p76其他相关论文其他相关论文77精神分裂症病理机制研究进展课件78免疫调节剂治疗精神分裂症的研究免疫调节剂治疗精神分裂症的研究n n接受利培酮治疗的首发精神分裂症接受利培酮治疗的首发精神分裂症celecoxibcelecoxib增效作用的双增效作用的双盲对照研究盲对照研究A double-blind,Placebo-controlled trial of celecoxib added to A double-blind,Placebo-controlled trial of celecoxib added to risperidone in treatment-nave,First episode patients with risperidone in treatment-nave,First episode patients with schizophrenia(Grant:03T-459)schizophrenia(Grant:03T-459)，200320032006;2006;n n青蒿素对精神分裂症的增效作用研究青蒿素对精神分裂症的增效作用研究A double-blind,placebo-controlled trial of artemisinin A double-blind,placebo-controlled trial of artemisinin added toadded to risperidone in treatment-nave,first episode patients with risperidone in treatment-nave,first episode patients with schizophrenia schizophrenia (Grant#:05T-726)(Grant#:05T-726)，200620062009.2009.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79精神分裂症病理机制研究进展课件80精神分裂症病理机制研究进展课件81精神分裂症病理机制研究进展课件82精神分裂症病理机制研究进展课件83精神分裂症病理机制研究进展课件84精神分裂症病理机制研究进展课件85精神分裂症病理机制研究进展课件86精神分裂症病理机制研究进展课件87精神分裂症病理机制研究进展课件881、YL Tan,DF Zhou,XY Zhang.Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia:association with dyskinetic movements.Schizophrenia Research,2005,74(2-3):176-183.（IF=4.072，2003）2、YL Tan,DF Zhou,LY Cao,YZ Zou,XY Zhang.Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychatics,Neuroscience Letters,2005,382(6):27-32.（IF=1.996，2003）3、YL Tan,DF Zhou,LY Cao,YZ Zou,XY Zhang.Association between the BDNFC270T polymorphism and negative symptoms of schizophrenia.Schizophrenia Research.2005,77:355-356.（IF=4.072，2003）4、YL Tan,DF Zhou,LY Cao,YZ Zou,XY Zhang.Effrct of the BDNF Val66Met genotype on episotic memory in schizophrenia.Schizophrenia Research.2005(in press).（IF=4.072，2003）1、YL Tan,DF Zhou,XY Zhang.D895、谭云龙，周东丰，张向阳等迟发性运动障碍患者血浆超氧化物歧化酶、过氧化化氢酶、谷胱苷肽过氧化物酶活性及丙二醛水平的改变中华精神科杂志，2005，38（3）：166168 6、谭云龙，周东丰，邹义壮等迟发性运动障碍患者血清泌乳素浓度分析中国心理卫生杂志，2005,19（7）：4634667、谭云龙，周东丰，邹义壮维生素E对迟发性运动障碍模型大鼠的影响中华精神科杂志，2004，37（3）：179 181.8、谭云龙，周东丰，邹义壮精神分裂症迟发性运动障碍患者BDNF研究中国神经精神疾病杂志，2004，30（5）：332-334.5、谭云龙，周东丰，张向阳等迟发性运动障碍患者血浆超氧化物909、谭云龙，曹连元，周东丰柴胡桃仁汤对迟发性运动障碍大鼠的治疗作用中国临床康复，2004，19（8）：38403842.10、谭云龙，曹连元，周东丰迟发性运动障碍的自由基研究新进展国外医学精神病学分册，2003，30（1）：48-51.13、谭云龙，周东丰，邹义壮抑郁症、强迫症、脑肿瘤患者威斯康星卡片分类测验操作比较中国心理卫生杂志，2003,17（9）:617-619.17、刘翠文，谭云龙，周东丰等伴发与非伴发迟发性运动障碍慢性精神分裂症患者认知状况的比较分析中国神经精神病杂志,2005,31（5）：329332.精神分裂症病理机制研究进展课件91 精神分裂症非药物治疗新技术的研究精神分裂症非药物治疗新技术的研究 北京市科委重大项目北京市科委重大项目，2006认知矫正治疗认知矫正治疗（Cognitive Remediation TherapyCognitive Remediation Therapy，CRTCRT）重复经颅磁刺激重复经颅磁刺激（Repetitive Transcranial Magnetic Stimulation，rTMS）认知行为治疗认知行为治疗（Cognitive-Behavioral Therapy，CBT）精神分裂症非药物治疗新技术的研究 认知矫正治疗（92研究背景 SCH非药物治疗SCH阳性症状阳性症状认知缺陷认知缺陷阴性症状阴性症状 解体 症状？情感症状？非药物治疗SCH康复的必需rTMS：低频治幻听低频治幻听CBT：妄想妄想CRT：认知矫正治疗认知矫正治疗rTMS：高频高频CBT：认知行为治疗认知行为治疗研究背景 SCH非药物治疗SCH阳性症状认知缺陷阴性症状93认知矫正治疗认知矫正治疗vv认知矫正治疗（认知矫正治疗（认知矫正治疗（认知矫正治疗（CRTCRT）：）：）：）：研究证实能显著改善精研究证实能显著改善精神分裂症的神分裂症的认知缺陷认知缺陷；改善灵活性和记忆；改善灵活性和记忆；认知矫正治疗认知矫正治疗（CRT）：研究证实能显著改善精神分94 精神分裂症认知矫正治疗（精神分裂症认知矫正治疗（精神分裂症认知矫正治疗（精神分裂症认知矫正治疗（CRTCRTCRTCRT）的前期研究）的前期研究）的前期研究）的前期研究：谭淑平博士课题：手册式认知矫正治疗的引进和初步疗效验证，证谭淑平博士课题：手册式认知矫正治疗的引进和初步疗效验证，证明其对慢性精神分裂症认知缺陷有效，社会功能有改善，同时对明其对慢性精神分裂症认知缺陷有效，社会功能有改善，同时对工作记忆相关脑区的认知激活情况有改善。工作记忆相关脑区的认知激活情况有改善。工作基础工作基础 CRT研究 精神分裂症认知矫正治疗（CRT）的前期研究：工作基础 95重复经颅磁刺激（rTMS）：n n功能失连接假说：脑功能改变？通过改变脑活动性发挥治疗作用n n低频治疗幻听，n n高频改善阴性症状；重复经颅磁刺激（rTMS）：功能失连接假说：脑功能改变？96 低频低频rTMSrTMS（1Hz1Hz）：）：抑制抑制作用，降低兴奋性，作用，降低兴奋性，对幻听对幻听有效有效;高频高频rTMS rTMS（20Hz20Hz）：）：兴奋兴奋作用，增强兴奋性，作用，增强兴奋性，对阴性对阴性症状有效症状有效;研究背景研究背景 低频rTMS（1Hz）：抑制作用，降低兴奋性，对幻听有971HzrTMS治疗组和空白对照组治疗组和空白对照组治疗前后治疗前后PANSS各项减分率比较各项减分率比较1Hz rTMS治疗组和空白对照组治疗前后PANSS各项减9820HzrTMS治疗组和空白对照组治疗组和空白对照组治疗前后治疗前后PANSS各项减分率比较各项减分率比较20Hz rTMS治疗组和空白对照组治疗前后PANSS各项99患者组治疗前与治疗后患者组治疗前与治疗后fMRI比较比较治疗前治疗后治疗前治疗后左侧边缘叶和扣带回 患者组治疗前与治疗后fMRI比较治疗前治疗后治疗前治疗后100vv对妄想症状有效对妄想症状有效（Medalia,2002Medalia,2002）；vv提高自知力及药物依从性，能改善阴性症状及提高自知力及药物依从性，能改善阴性症状及精神分裂症后抑郁等精神分裂症后抑郁等(Rector,2003)(Rector,2003)；vv能改善精神分裂症的继发情绪问题能改善精神分裂症的继发情绪问题（陈恩民（陈恩民,2003,2003）研究背景研究背景 国外国外CBTCBT研究现状研究现状对妄想症状有效（Medalia,2002）；研究背景 国101n n安定医院李占江等已开展的前期工作制定了对精神分裂症的CBT治疗方案和初步临床评估研究背景 国内CBT研究现状安定医院李占江等已开展的前期工作制定了对精神分裂症的CBT治102非药物治疗的共同点非药物治疗的共同点n n旨在发展有增效作用的非药物治疗新技术n n在原有药物治疗的基础上进行n n治疗前后脑功能影像测量n n短期疗效和长期随访相结合非药物治疗的共同点旨在发展有增效作用的非药物治疗新技术103