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1、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3abnormal geneINHERITED DISEASE100% will develop the inherited disease (classical autosomal dominant pattern)4-1Stahl S M, Essential Psychopharmacology (2000)abnormal gene produ
2、ct4RISK 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
3、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)5LIFE EVENTSFILTERpersonality/coping skillsgenetic vulnerabili
4、ty factors for depression4-3Stahl S M, Essential Psychopharmacology (2000)6even 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
5、 (2000)7MINOR 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)8
6、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9good neuronal selection= healthy neuron= defective neuronbad neuronal selection4-6选择异常选择异常10bad migrationgood migration4-7迁移异常迁移异常11normal DNAnormal DNA12正确连线正确连线13abnormal DNAabnormal DNA14错误连线错误连线4-9Stahl S M, Essential sychopharmacology (2000)15神经传递异常的表现神经传递异
7、常的表现16hypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M, Essential Psychopharmacology (2000)17mesolimbic pathway10-8Stahl S M, Essential Psychopharmacology (2000)18mesolimbic overactivity = positive symptoms of psychosis10-9Stahl S M, Essential Psy
8、chopharmacology (2000)19meso-cortical pathway10-10Stahl S M, Essential Psychopharmacology (2000)20primary dopamine deficiencyD2 receptor blockadesecondary dopamine deficiencymesocortical pathwayincrease in negative symptoms10-11Stahl S M, Essential Psychopharmacology (2000)21nigrostriatal pathway22t
9、ubero infundibular pathway23positive symptomspsychotic depressionbipolarchildhood psychotic illnessesschizo- affectiveAlzheimers10-2Stahl S M, Essential Psychopharmacology (2000)24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25D2pure D2 blocker11-1经典抗精神病药物经典抗精神病药物26pur
10、e D2 blocker11-2Stahl S M, Essential Psychopharmacology (2000)27Increase in negative symptoms11-3Stahl S M, Essential Psychopharmacology (2000)Mesocortical pathway28EPSs11-4Stahl S M, Essential Psychopharmacology (2000)Nigrostriatal pathway29Blockade of receptors in the nigrostriatal dopamine pathwa
11、y causes them to up-regulateThis up-regulation may lead to tardive dyskinesia11-5Stahl S M, Essential Psychopharmacology (2000)30Prolactin levels rise11-6Stahl S M, Essential Psychopharmacology (2000)Tuberoinfundibular pathway31H1M1D21conventional antipsychotic drug11-7Stahl S M, Essential Psychopha
12、rmacology (2000)32constipationLAXATIVEblurred visiondry mouthdrowsiness11-8Stahl S M, Essential Psychopharmacology (2000)M1 INSERTED33= acetylcholine= dopamine11-9Stahl S M, Essential Psychopharmacology (2000)34= D2 blocker11-10Stahl S M, Essential Psychopharmacology (2000)35= anticholinergic11-11St
13、ahl S M, Essential Psychopharmacology (2000)36H1 INSERTED11-12Stahl S M, Essential Psychopharmacology (2000)drowsinessweight gain37drowsinessdecreased blood pressuredizziness11-13Stahl S M, Essential Psychopharmacology (2000)1 INSERTED381D2haloperidol11-15395HT2AD2SDA11-16SDA405HT7125HT2AD2risperido
14、ne 11-39Stahl S M, Essential Psychopharmacology (2000)415HT-DA Interactions11-17Stahl S M, Essential Psychopharmacology (2000)Substantia nigraraphe nucleusbrakebrake42conventional antipsychoticcaudate nucleus11-25Stahl S M, Essential Psychopharmacology (2000)43serotonin-dopamine antagonistcaudate nu
15、cleus11-26Stahl S M, Essential Psychopharmacology (2000)44conventional antipsychoticCortex11-28Stahl S M, Essential Psychopharmacology (2000)45serotonin-dopamine antagonistCortex11-29Stahl S M, Essential Psychopharmacology (2000)465HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine 11-37多受体机制药物多受体机制药
16、物475HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine 11-40Stahl S M, Essential Psychopharmacology (2000)485HT75HT6H1125HT2AD2quetiapine 11-41Stahl S M, Essential Psychopharmacology (2000)49Are Antipsychotics with Multiple Therapeutic Mechanisms Better than Selective Dopamine 2 Antagonists?11-35Stahl S M, Es
17、sential Psychopharmacology (2000)multiple mechanisms = side effectschlorpromazinesingle selective mechanisms = loss of side effectsHaloperidolmultiple therapeutic mechanisms = improved efficacyclozapineSDArisperidonequetiapineolanzapine50DA部分激动剂或部分激动剂或DA稳定剂稳定剂51hypothalamusdcNucleus accumbensTegment
18、umbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M, Essential Psychopharmacology (2000)52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54agonistanxiolyticsedative hypnotic
19、muscle relaxantanticonvulsantamnesticdependencypartial agonistanxiolytic onlyantagonistno clinical effectpartial inverse agonistpromnestic (memory enhancing) anxiogenicinverse agonistpromnesticanxiogenic pro-convulsant8-25Stahl S M, Essential Psychopharmacology (2000)55FULL AGONIST - light is at its
20、 brightest3-15Stahl S M, Essential Psychopharmacology (2000)56PARTIAL AGONIST - light is dimmed but still shining3-16Stahl S M, Essential Psychopharmacology (2000)57NO AGONIST - light is off3-17Stahl S M, Essential Psychopharmacology (2000)58PARTIAL AGONIST - light is dimmed but still shining3-16Sta
21、hl S M, Essential Psychopharmacology (2000)59神经退行性变神经退行性变n n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61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
22、天因素导致免疫过度激活n n神经过度兴奋的毒性作用钙离子大量内流自由基大量生成细胞死亡62abnormal gene product10-18Stahl S M, Essential Psychopharmacology (2000)63over excitation due to glutamate10-27Stahl S M, Essential Psychopharmacology (2000)64excess calcium activates enzyme10-28Stahl S M, Essential Psychopharmacology (2000)65enzyme produ
23、ces free radicalthe end is near10-29Stahl S M, Essential Psychopharmacology (2000)66free radicals begin destroying the cell10-30Stahl S M, Essential Psychopharmacology (2000)67finally, free radicals destroy the cell10-31Stahl S M, Essential Psychopharmacology (2000)6810-20Stahl S M, Essential Psycho
24、pharmacology (2000)apoptosis/ necrosis100% 50% 01520406069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免疫调节剂自由基俘获剂或清除剂非药物治疗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71Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients
25、 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72Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology(Zhang,Zhouetal,SchizophreniaResearch200
26、2)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
27、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75T
28、umour 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76其他相关论文7778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, Plac
29、ebo-controlled trial of celecoxib added A double-blind, Placebo-controlled trial of celecoxib added to risperidone in treatment-nato risperidone in treatment-na ve, First episode patients ve, First episode patients with schizophrenia (Grant: 03T-459) with schizophrenia (Grant: 03T-459) ，200320032006
30、;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-na risperidone in treatment-na ve, first episode patients with ve, first episode patients with schizophre
31、nia schizophrenia (Grant #: 05T-726) (Grant #: 05T-726)，200620062009.2009.798081828384858687881、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,2005,7
32、4(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 betw
33、een 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
34、）895、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）：332-334.909、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
35、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）：329332.91 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
36、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） 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
37、CBT：认知行为治疗认知行为治疗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；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
38、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；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971HzrTM
39、S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 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103
