精神分裂症病理机制的研究进展

1、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 metabolize neurotransmitters when release is very fas

2、trisk 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 gene

3、tic 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 you inherit the gene for schizophrenia,

4、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 biologically determined)schizophreniamoderate str

5、essors(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 selection选择异常选择异常bad migrationgood migration迁移异常迁移异常nor

6、mal dnanormal dna正确连线正确连线abnormal dnaabnormal dna错误连线错误连线4-9stahl s m, essential sychopharmacology (2000)hypothalamusdcnucleus accumbenstegmentumbsubstantia nigrabasal gangliaadopamine pathways10-7stahl s m, essential psychopharmacology (2000)mesolimbic pathway10-8stahl s m, essential psychopharmaco

7、logy (2000)mesolimbic overactivity = positive symptoms of psychosis10-9stahl s m, essential psychopharmacology (2000)meso-cortical pathway10-10stahl s m, essential psychopharmacology (2000)primary dopamine deficiencyd2 receptor blockadesecondary dopamine deficiencymesocortical pathwayincrease in neg

8、ative symptoms10-11stahl s m, essential psychopharmacology (2000)nigrostriatal pathwaytubero infundibular pathwaypositive symptomspsychotic depressionbipolarchildhood psychotic illnessesschizo- affectivealzheimers10-2stahl s m, essential psychopharmacology (2000)d2pure d2 blocker经典抗精神病药物经典抗精神病药物pure

9、 d2 blocker11-2stahl s m, essential psychopharmacology (2000)increase in negative symptoms11-3stahl s m, essential psychopharmacology (2000)mesocortical pathwayepss11-4stahl s m, essential psychopharmacology (2000)nigrostriatal pathwayblockade of receptors in the nigrostriatal dopamine pathway cause

10、s them to up-regulatethis up-regulation may lead to tardive dyskinesia11-5stahl s m, essential psychopharmacology (2000)prolactin levels rise11-6stahl s m, essential psychopharmacology (2000)tuberoinfundibular pathwayh1m1d21conventional antipsychotic drug11-7stahl s m, essential psychopharmacology (

11、2000)constipationlaxativeblurred visiondry mouthdrowsiness11-8stahl s m, essential psychopharmacology (2000)m1 inserted= acetylcholine= dopamine11-9stahl s m, essential psychopharmacology (2000)= d2 blocker11-10stahl s m, essential psychopharmacology (2000)= anticholinergic11-11stahl s m, essential

12、psychopharmacology (2000)h1 inserted11-12stahl s m, essential psychopharmacology (2000)drowsinessweight gaindrowsinessdecreased blood pressuredizziness11-13stahl s m, essential psychopharmacology (2000)1 inserted1d2haloperidol5ht2ad2sdasda5ht7125ht2ad2risperidone 11-39stahl s m, essential psychophar

13、macology (2000)5ht-da interactions11-17stahl s m, essential psychopharmacology (2000)substantia nigraraphe nucleusbrakebrakeconventional antipsychoticcaudate nucleus11-25stahl s m, essential psychopharmacology (2000)serotonin-dopamine antagonistcaudate nucleus11-26stahl s m, essential psychopharmaco

14、logy (2000)conventional antipsychoticcortex11-28stahl s m, essential psychopharmacology (2000)serotonin-dopamine antagonistcortex11-29stahl s m, essential psychopharmacology (2000)5ht75ht65ht35ht2c5ht1am1h112d1d3d45ht2ad2clozapine 多受体机制药物多受体机制药物5ht65ht35ht2cm1h11d1d3d45ht2ad2olanzapine 11-40stahl s

15、m, essential psychopharmacology (2000)5ht75ht6h1125ht2ad2quetiapine 11-41stahl s m, essential psychopharmacology (2000)are antipsychotics with multiple therapeutic mechanisms better than selective dopamine 2 antagonists?11-35stahl s m, essential psychopharmacology (2000)multiple mechanisms = side ef

16、fectschlorpromazinesingle selective mechanisms = loss of side effectshaloperidolmultiple therapeutic mechanisms = improved efficacyclozapinesdarisperidonequetiapineolanzapinehypothalamusdcnucleus accumbenstegmentumbsubstantia nigrabasal gangliaadopamine pathways10-7stahl s m, essential psychopharmac

17、ology (2000)agonistanxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependencypartial agonistanxiolytic onlyantagonistno clinical effectpartial inverse agonistpromnestic (memory enhancing) anxiogenicinverse agonistpromnesticanxiogenic pro-convulsant8-25stahl s m, essential psychopharm

18、acology (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 agonist - li

19、ght is dimmed but still shining3-16stahl s m, essential psychopharmacology (2000)“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.”4-22abnormal gene product10-18stahl s m, essential psychopharmacology

20、(2000)over 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)free radicals begin destroying the

21、cell10-30stahl s m, essential psychopharmacology (2000)finally, free radicals destroy the cell10-31stahl s m, essential psychopharmacology (2000)10-20stahl s m, essential psychopharmacology (2000)apoptosis/ necrosis100% 50% 015204060decreased production of interleukin-2 (il-2), il-2 secreting cells

22、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elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology

23、(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 cli

24、nical 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 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

25、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tumournecrosisfactoralphapolymorphism(-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5. 张向阳; 周东丰; 沈渔村; 等: 精神分裂症神经内分泌、免疫、自由基代谢与治疗药物的关系.中华精神科杂志 1999; 32 (4) 212-215 (被引用 7 次)6张向阳; 周东丰; 向义安等 (199

26、8): 孤独症与精神分裂症患者异常淋巴细胞的对照研究. 中华精神科杂志 31(1): 26-29 (被引用 1 次)7. 张向阳; 周东丰 (1997). 人类白细胞抗原在精神分裂症和抗精神病药副作用中的研究进展. 中华精神科杂志 30(2): 118-120 (unknown)8. 张向阳, 周东丰, 张培琰等(1997): 精神分裂症免疫指标与精神症状的关系.中华精神科杂志 30(3): 145-148 (被引用 6 次)9. 张向阳, 周东丰, 张培琰等(1996): 慢性精神分裂症病人的免疫功能测定. 中华精神科杂志29(4): 205-208 (被引用 17 次)10张向阳, 周东丰

27、, 沈渔村等 (2000). 利培酮和氟哌啶醇对精神分裂症白细胞介素的作用及其与疗效.中国神经精神疾病杂志 26 (4): 222-224 (被引用 7 次)11.张向阳, 周东丰, 张培琰等 (1999): 精神分裂症白细胞介素 2 和 cd4+细胞的相关研究. 中国神经精神疾病杂志 25(5): 268-270 (被引用 5 次)12. 张向阳, 周东丰, 沈渔村等 (1999). 精神分裂症白细胞介素 2、6、8 与精神病理的关系.中国神经精神疾病杂志 25 (6): 346-348 (被引用 10 次)13.张向阳, 周东丰 (1996): 白细胞介素在精神分裂症中的研究进展. 国外医

28、学精神病学分册.23(4): 211-215 (被引用 6 次)14. 张向阳, 周东丰 (1995): 精神分裂症的免疫学研究进展. 国外医学精神病学分册. 22(2): 74-79(被引用 6 次)37. zhang xy, zhou df, cao ly, et al. the effect of vitamin etreatment on tardive dyskinesia and blood superoxidedismutase: a double-blind placebo-controlled trial.journal of clinical psychopharmacol

29、ogy 2004;24 (1): 83-86 (times cited 1). 38. zhang xy, zhou df, cao ly, et al. blood superoxidedismutase level in schizophrenic patients with tardivedyskinesia: association with dyskinetic movements. schizophrenia research 2003; 62 (3): 245-250(times cited 4).1、yl tan, df zhou, xy zhang. decreased pl

30、asma 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 schizophreni

31、a 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）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