精神分裂癥病理機制研究進展課件

1、精神分裂癥病理機制的研究進展和治療學發(fā)展精神分裂癥病理機制的研究進展和治療學發(fā)展基本病理機制神經(jīng)發(fā)育異常神經(jīng)傳遞異常神經(jīng)退行性變基本病理機制神經(jīng)發(fā)育異常有關發(fā)育異常遺傳和環(huán)境相互作用 遺傳方式尚不清楚，多基因遺傳可能性大有關發(fā)育異常遺傳和環(huán)境相互作用abnormal geneINHERITED DISEASE100% will develop the inherited disease (classical autosomal dominant pattern)4-1Stahl S M, Essential Psychopharmacology (2000)abnormal gene prod

2、uctabnormal geneINHERITED DISEASERISK 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

3、 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 2RISKLI

4、FE EVENTSFILTERpersonality/coping skillsgenetic vulnerability factors for depression4-3Stahl S M, Essential Psychopharmacology (2000)LIFE EVENTSFILTERpersonality/ceven if you inherit the gene for Schizophrenia, the chances of whether or not you develop the disease may be affected by outside factorsb

5、ad childhooddivorcevirus or toxinschizophrenia4-4Stahl S M, Essential Psychopharmacology (2000)even if you inherit the gene fMINOR STRESSORS(DNA with predisposition for schizophrenia - highly biologically determined)SCHIZOPHRENIAMODERATE STRESSORS(DNA with predisposition for depression - moderately

6、biologically determined)DEPRESSIONMAJOR STRESSORS(“normal” DNA)PTSD4-5Stahl S M, Essential Psychopharmacology (2000)MINOR STRESSORS(DNA with predi發(fā)育異常的表現(xiàn)選擇異常遷移異常突觸連接異常發(fā)育異常的表現(xiàn)選擇異常good neuronal selection= healthy neuron= defective neuronbad neuronal selection4-6選擇異常good neuronal selection= healtbad mi

7、grationgood migration4-7遷移異常bad migrationgood migration4-7normal DNAnormal DNAnormal DNAnormal DNA正確連線正確連線abnormal DNAabnormal DNAabnormal DNAabnormal DNA錯誤連線4-9Stahl S M, Essential sychopharmacology (2000)錯誤連線4-9Stahl S M, Essential sy神經(jīng)傳遞異常的表現(xiàn)神經(jīng)傳遞異常的表現(xiàn)hypothalamusdcNucleus accumbensTegmentumbSubst

8、antia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M, Essential Psychopharmacology (2000)hypothalamusdcNucleus accumbenmesolimbic pathway10-8Stahl S M, Essential Psychopharmacology (2000)mesolimbic pathway10-8Stahl S mesolimbic overactivity = positive symptoms of psychosis10-9Stahl S M, Essential

9、 Psychopharmacology (2000)mesolimbic overactivity = posimeso-cortical pathway10-10Stahl S M, Essential Psychopharmacology (2000)meso-cortical pathway10-10Stahprimary dopamine deficiencyD2 receptor blockadesecondary dopamine deficiencymesocortical pathwayincrease in negative symptoms10-11Stahl S M, E

10、ssential Psychopharmacology (2000)primary dopamine deficiencyD2 nigrostriatal pathwaynigrostriatal pathwaytubero infundibular pathwaytubero infundibular pathwaypositive symptomspsychotic depressionbipolarchildhood psychotic illnessesschizo- affectiveAlzheimers10-2Stahl S M, Essential Psychopharmacol

11、ogy (2000)positive symptomspsychotic dep精神分裂癥的治療機制經(jīng)典抗精神病藥物純D2受體阻斷劑SDADA2/5TH2受體阻斷劑多受體機制藥物DA穩(wěn)定劑精神分裂癥的治療機制經(jīng)典抗精神病藥物純D2受體阻斷劑D2pure D2 blocker11-1經(jīng)典抗精神病藥物D2pure D2 blocker11-1經(jīng)典抗精神病藥物pure D2 blocker11-2Stahl S M, Essential Psychopharmacology (2000)pure D2 blocker11-2Stahl S M, Increase in negative sympto

12、ms11-3Stahl S M, Essential Psychopharmacology (2000)Mesocortical pathwayIncrease in negative symptoms1EPSs11-4Stahl S M, Essential Psychopharmacology (2000)Nigrostriatal pathwayEPSs11-4Stahl S M, Essential PBlockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulateThis up

13、-regulation may lead to tardive dyskinesia11-5Stahl S M, Essential Psychopharmacology (2000)Blockade of receptors in the nProlactin levels rise11-6Stahl S M, Essential Psychopharmacology (2000)Tuberoinfundibular pathwayProlactin levels rise11-6StahlH1M1D21conventional antipsychotic drug11-7Stahl S M

14、, Essential Psychopharmacology (2000)H1M1D21conventional antipsychoconstipationLAXATIVEblurred visiondry mouthdrowsiness11-8Stahl S M, Essential Psychopharmacology (2000)M1 INSERTEDconstipationLAXATIVEblurred vi= acetylcholine= dopamine11-9Stahl S M, Essential Psychopharmacology (2000)= acetylcholin

15、e= dopamine11-9S= D2 blocker11-10Stahl S M, Essential Psychopharmacology (2000)= D2 blocker11-10Stahl S M, Es= anticholinergic11-11Stahl S M, Essential Psychopharmacology (2000)= anticholinergic11-11Stahl S H1 INSERTED11-12Stahl S M, Essential Psychopharmacology (2000)drowsinessweight gainH1 INSERTE

16、D11-12Stahl S M, Essdrowsinessdecreased blood pressuredizziness11-13Stahl S M, Essential Psychopharmacology (2000)1 INSERTEDdrowsinessdecreased blood pres1D2haloperidol11-151D2haloperidol11-155HT2AD2SDA11-16SDA5HT2AD2SDA11-16SDA5HT7125HT2AD2risperidone 11-39Stahl S M, Essential Psychopharmacology (2

17、000)5HT7125HT2AD2risperidone 11-35HT-DA Interactions11-17Stahl S M, Essential Psychopharmacology (2000)Substantia nigraraphe nucleusbrakebrake5HT-DA Interactions11-17Stahl conventional antipsychoticcaudate nucleus11-25Stahl S M, Essential Psychopharmacology (2000)conventional antipsychoticcaudseroto

18、nin-dopamine antagonistcaudate nucleus11-26Stahl S M, Essential Psychopharmacology (2000)serotonin-dopamine antagonistcconventional antipsychoticCortex11-28Stahl S M, Essential Psychopharmacology (2000)conventional antipsychoticCortserotonin-dopamine antagonistCortex11-29Stahl S M, Essential Psychop

19、harmacology (2000)serotonin-dopamine antagonistC5HT75HT65HT35HT2C5HT1AM1H112D1D3D45HT2AD2clozapine 11-37多受體機制藥物5HT75HT65HT35HT2C5HT1AM1H112D15HT65HT35HT2CM1H11D1D3D45HT2AD2olanzapine 11-40Stahl S M, Essential Psychopharmacology (2000)5HT65HT35HT2CM1H11D1D3D45HT2AD5HT75HT6H1125HT2AD2quetiapine 11-41S

20、tahl S M, Essential Psychopharmacology (2000)5HT75HT6H1125HT2AD2quetiapine Are Antipsychotics with Multiple Therapeutic Mechanisms Better than Selective Dopamine 2 Antagonists?11-35Stahl S M, Essential Psychopharmacology (2000)multiple mechanisms = side effectschlorpromazinesingle selective mechanis

21、ms = loss of side effectsHaloperidolmultiple therapeutic mechanisms = improved efficacyclozapineSDArisperidonequetiapineolanzapineAre Antipsychotics with MultipDA部分激動劑或DA穩(wěn)定劑DA部分激動劑或DA穩(wěn)定劑hypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M, Essential P

22、sychopharmacology (2000)hypothalamusdcNucleus accumben精神分裂癥的多巴胺假說 高多巴胺通路 低多巴胺通路 陽性癥狀 陰性癥狀精神分裂癥的多巴胺假說多巴胺部分激動的原理對于多巴胺功能失調(diào)理想的治療 - 降低中腦邊緣通路的多巴胺活性 - 增強中腦皮質(zhì)通路的多巴胺活性 - 不影響結節(jié)漏斗部通路和黑質(zhì)紋狀體通路多巴胺部分激動的原理對于多巴胺功能失調(diào)理想的治療agonistanxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependencypartial agonista

23、nxiolytic onlyantagonistno clinical effectpartial inverse agonistpromnestic (memory enhancing) anxiogenicinverse agonistpromnesticanxiogenic pro-convulsant8-25Stahl S M, Essential Psychopharmacology (2000)agonistanxiolyticpartial agoniFULL AGONIST - light is at its brightest3-15Stahl S M, Essential

24、Psychopharmacology (2000)FULL AGONIST - light is at itPARTIAL AGONIST - light is dimmed but still shining3-16Stahl S M, Essential Psychopharmacology (2000)PARTIAL AGONIST - light is diNO AGONIST - light is off3-17Stahl S M, Essential Psychopharmacology (2000)NO AGONIST - light is off3-17PARTIAL AGON

25、IST - light is dimmed but still shining3-16Stahl S M, Essential Psychopharmacology (2000)PARTIAL AGONIST - light is di神經(jīng)退行性變凋亡和壞死神經(jīng)退行性變凋亡和壞死“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.”4-22DA過度傳遞引

26、起細胞凋亡“pruning” out of controlA dise神經(jīng)退行性變細胞死亡GABA神經(jīng)元發(fā)育不足，谷氨酸神經(jīng)元過渡釋放先天因素和后天因素導致免疫過度激活神經(jīng)過度興奮的毒性作用鈣離子大量內(nèi)流自由基大量生成細胞死亡神經(jīng)退行性變細胞死亡GABA神經(jīng)元發(fā)育不足，谷氨酸神經(jīng)元abnormal gene product10-18Stahl S M, Essential Psychopharmacology (2000)abnormal gene product10-18Stahover excitation due to glutamate10-27Stahl S M, Essential

27、 Psychopharmacology (2000)over excitation due to glutamaexcess calcium activates enzyme10-28Stahl S M, Essential Psychopharmacology (2000)excess calcium activates enzymenzyme produces free radicalthe end is near10-29Stahl S M, Essential Psychopharmacology (2000)enzyme produces free radicalthfree rad

28、icals begin destroying the cell10-30Stahl S M, Essential Psychopharmacology (2000)free radicals begin destroyingfinally, free radicals destroy the cell10-31Stahl S M, Essential Psychopharmacology (2000)finally, free radicals destroy10-20Stahl S M, Essential Psychopharmacology (2000)apoptosis/ necros

29、is100% 50% 01520406010-20Stahl S M, Essential Psyc精神分裂癥治療藥物治療，主要改變傳遞異常，不能改變發(fā)育異常和阻斷退行性變針對退行性變的非抗精神病藥物治療免疫調(diào)節(jié)劑自由基俘獲劑或清除劑非藥物治療精神分裂癥治療藥物治療，主要改變傳遞異常，不能改變發(fā)育異常和免疫異常和免疫調(diào)節(jié)劑治療既往研究發(fā)現(xiàn)精神分裂癥免疫過度激活免疫異常和免疫調(diào)節(jié)劑治療既往研究發(fā)現(xiàn)精神分裂癥免疫過度激活Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medic

30、ation-free patients with schizophrenia (Zhang, Zhou et al, Journal of Psychiatric Research 2002)研究發(fā)現(xiàn)精神分裂癥患者存在IL-2 產(chǎn)物生成降低，與T細胞數(shù)目減少， IL-2分泌減少有關精神分裂癥病理機制研究進展課件Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology(Zhang,

31、Zhou et al, Schizophrenia Research 2002)研究進一步發(fā)現(xiàn)未服抗精神病藥物的不同亞型精神分裂癥患者細胞因子改變不同精神分裂癥病理機制研究進展課件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)

32、典型和非典型抗精神病藥物均部分改善精神分裂癥患者的細胞因子異常，且基線的細胞因子水平可預測藥物療效精神分裂癥病理機制研究進展課件Cortisol and Cytokines in Chronic and Treatment-Resistant Patients with Schizophrenia: Association with Psychopathology and Response to Antipsychotics (Zhang, Zhou et al, Neuropsychopharmacology 2005)未服抗精神病藥物的患者細胞因子的改變與其HPA軸功能紊亂相關，且經(jīng)過藥物

33、治療改善后這些改變趨于正常，提示這些改變是癥狀相關的精神分裂癥病理機制研究進展課件Tumour necrosis factor alpha polymorphism (-1031T/C) is associated with age of onset of schizophrenia.(Zhang et al, Molecular Psychiatry 2005)腫瘤壞死因子alpha基因1 1031T/C多態(tài)性與早發(fā)型精神分裂癥有關Tumour necrosis factor alpha p其他相關論文其他相關論文精神分裂癥病理機制研究進展課件免疫調(diào)節(jié)劑治療精神分裂癥的研究接受利培酮治療的首

34、發(fā)精神分裂癥celecoxib增效作用的雙盲對照研究A double-blind, Placebo-controlled trial of celecoxib added to risperidone in treatment-nave, First episode patients with schizophrenia (Grant: 03T-459) ，20032006;青蒿素對精神分裂癥的增效作用研究A double-blind, placebo-controlled trial of artemisinin added to risperidone in treatment-nave,

35、 first episode patients with schizophrenia (Grant #: 05T-726)，20062009.免疫調(diào)節(jié)劑治療精神分裂癥的研究接受利培酮治療的首發(fā)精神分裂癥精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件精神分裂癥病理機制研究進展課件1、YL Tan, DF Zhou, XY Zhang. Decreased plasma brain-derived neur

36、otrophic 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 treatmen

37、t 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 Z

38、ou, 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. D5、譚云龍，周東豐，張向陽等遲發(fā)性運動障礙患者血漿超氧化物歧化酶、過氧化化氫酶、谷胱苷肽過氧化物酶活性及丙二醛水平的改變中華精神科雜志，2005，38（3）：166168 6、譚云龍，周東豐，鄒義壯等遲發(fā)性運動障礙患者血清泌乳素濃度分析中國心理衛(wèi)生雜志，

39、2005,19（7）：4634667、譚云龍，周東豐，鄒義壯維生素E對遲發(fā)性運動障礙模型大鼠的影響中華精神科雜志，2004，37（3）：179 181.8、譚云龍，周東豐，鄒義壯精神分裂癥遲發(fā)性運動障礙患者BDNF研究中國神經(jīng)精神疾病雜志，2004，30（5）：332-334.5、譚云龍，周東豐，張向陽等遲發(fā)性運動障礙患者血漿超氧化物9、譚云龍，曹連元，周東豐柴胡桃仁湯對遲發(fā)性運動障礙大鼠的治療作用中國臨床康復，2004，19（8）：38403842.10、譚云龍，曹連元，周東豐遲發(fā)性運動障礙的自由基研究新進展國外醫(yī)學精神病學分冊，2003，30（1）：48-51.13、譚云龍，周東豐，鄒義壯抑郁癥、強迫癥、腦腫瘤患者威斯康星卡片分類測驗操作比較中國心理衛(wèi)生雜志，2003,17（9）:617-619.17、劉