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 fastRIS
2、K 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 responsesRI
3、SK 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,the chances of whethe
4、r 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 STRESSORS(DNA with predispos
5、ition 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normal DNAnormal DNA正确连线正确连线abnorma
6、l 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 Psychopharmacology(2000)mesolimbic overactivity=pos
7、itive 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 negative symptoms10-11Stahl S M,Essential Psych
8、opharmacology(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 D2 blocker11-2Stahl S M,Essential Psychopharmaco
9、logy(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 causes them to up-regulateThis up-regulation may lead to tar
10、dive 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(2000)constipationLAXATIVEblurred visiondry mouthdrowsiness11-
11、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 Psychopharmacology(2000)H1 INSERTED11-12Stahl S M,Essential Psychopharma
12、cology(2000)drowsinessweight gaindrowsinessdecreased blood pressuredizziness11-13Stahl S M,Essential Psychopharmacology(2000)1 INSERTED1D2haloperidol5HT2AD2SDASDA5HT7125HT2AD2risperidone 11-39Stahl S M,Essential Psychopharmacology(2000)5HT-DA Interactions11-17Stahl S M,Essential Psychopharmacology(2
13、000)Substantia nigraraphe nucleusbrakebrakeconventional antipsychoticcaudate nucleus11-25Stahl S M,Essential Psychopharmacology(2000)serotonin-dopamine antagonistcaudate nucleus11-26Stahl S M,Essential Psychopharmacology(2000)conventional antipsychoticCortex11-28Stahl S M,Essential Psychopharmacolog
14、y(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 M,Essential Psychopharmacology(2000)5HT75HT6H1125HT2AD2quetiapine 11-41Stahl S M,Essentia
15、l Psychopharmacology(2000)Are 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 therapeuti
16、c mechanisms=improved efficacyclozapineSDArisperidonequetiapineolanzapinehypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS10-7Stahl S M,Essential Psychopharmacology(2000)agonistanxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependencypartial ag
17、onistanxiolytic onlyantagonistno clinical effectpartial inverse agonistpromnestic(memory enhancing)anxiogenicinverse agonistpromnesticanxiogenic pro-convulsant8-25Stahl S M,Essential Psychopharmacology(2000)FULL AGONIST-light is at its brightest3-15Stahl S M,Essential Psychopharmacology(2000)PARTIAL
18、 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-light is dimmed but still shining3-16Stahl S M,Essential Psychopharmacology(2000)“pruning”out of controlA disease may let t
19、he 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(2000)over excitation due to glutamate10-27Stahl S M,Essential Psychopharmacology(2000)excess calcium activates enzyme10-28Stahl
20、 S M,Essential Psychopharmacology(2000)enzyme produces free radicalthe end is near10-29Stahl S M,Essential Psychopharmacology(2000)free radicals begin destroying the cell10-30Stahl S M,Essential Psychopharmacology(2000)finally,free radicals destroy the cell10-31Stahl S M,Essential Psychopharmacology
21、(2000)10-20Stahl S M,Essential Psychopharmacology(2000)apoptosis/necrosis100%50%015204060Decreased 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
22、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,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 l
23、evels 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 and Treatment-Resistant Patients with Schizophrenia:Asso
24、ciation 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Tumournecrosisfactoralphapolymorphism(-1031T/C)isassociatedwithageofonsetofschizophrenia.(Zhangetal,MolecularPsychiatry2005)肿瘤坏死因子al
25、pha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(1998):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 3
26、0(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,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
27、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 p
28、lacebo-controlled trial.JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 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
29、 4).1、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 o
30、f 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.
31、（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清泌乳素浓度分析中
32、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）：332-334.9、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
33、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）SCH阳性症状阳性症状认知
34、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010203040506070*Cognition Improvement Rate ComparingCognition Improvement RateCognitive Flexibility Memory Executive Function CRT Con工作基础工作基础 CRT研究 低频低频rTMSrTMS（1Hz1Hz）：）：;高频高频rTMS rTMS（20Hz20Hz）：）：;研究背景研究背景01020304050幻听阳性阴性一般总分1Hz治疗前后PANSS减分率比较治疗组对照组05101520253035阳性阴性一般总体20Hz治疗的减分率比较治疗组对照组治疗前治疗后治疗前治疗后左侧边缘叶和扣带回 研究背景研究背景 国外国外CBTCBT研究现状研究现状
