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1、精神分裂症病理机制的研究进展和治疗学发展,北京大学精神卫生研究所 周东丰,基本病理机制,神经发育异常 神经传递异常 神经退行性变,有关发育异常,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,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 depressio
2、n,发育异常的表现,选择异常 迁移异常 突触连接异常,normal DNA,normal DNA,正确连线,abnormal DNA,abnormal DNA,错误连线,神经传递异常的表现,c,DOPAMINE PATHWAYS,mesolimbic pathway,mesolimbic overactivity = positive symptoms of psychosis,meso-cortical pathway,primary dopamine deficiency,D2 receptor blockade,secondary dopamine deficiency,mesocort
3、ical pathway,increase in negative symptoms,nigrostriatal pathway,tubero infundibular pathway,positive symptoms,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 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
4、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 Inte
5、ractions,conventional antipsychotic,caudate nucleus,serotonin-dopamine antagonist,caudate nucleus,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,
6、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 br
7、ightest,PARTIAL AGONIST - light is dimmed but still shining,NO AGONIST - light is off,PARTIAL AGONIST - light is dimmed but still shining,神经退行性变,凋亡和坏死,“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.
8、”,神经退行性变细胞死亡,GABA神经元发育不足，谷氨酸神经元过渡释放 先天因素和后天因素导致免疫过度激活 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,abnormal gene product,over excitation due to glutamate,excess calcium activates enzyme,enzyme produces free radical,the end is near,free radicals begin destroying the cell,finally, free radicals destroy the cell,a
9、poptosis/ necrosis,100%,50%,0,15,20,40,60,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阻断退行性变 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,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,Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients with schizophrenia (Zhang, Zhou et al,
10、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,Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology (Zhang, Zhou et al, Schizophrenia Research 2002) 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
11、子改变不同,Changes 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,Cortisol and Cytokines in Chronic
12、 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,Tumour necrosis factor alpha polymorphism (-1031T/C) is associated wi
13、th age of onset of schizophrenia. (Zhang et al, Molecular Psychiatry 2005) 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,其他相关论文,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celecoxib增效作用的双盲对照研究 A double-blind, Placebo-controlled trial of celecoxib added to risperidone in treatment-nave, First episode patients with schizop
14、hrenia (Grant: 03T-459) ，20032006; 青蒿素对精神分裂症的增效作用研究,A double-blind, placebo-controlled trial of artemisinin added to risperidone in treatment-nave, first episode patients with schizophrenia (Grant #: 05T-726)，20062009.,1、YL Tan, DF Zhou, XY Zhang. Decreased plasma brain-derived neurotrophic factor l
15、evels 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 antipsych
16、atics, 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. Schizop
