zz导论 -schizo-depression

1、神经精神疾病张 智2013.11.7抑郁症患病率国内约4%，国外10%，年患病率10.3%。疾病医疗负担排名：抑郁症占第1位 (中国)人群分布：女：男=2：1，在人际关系不良，独居，离婚者中比一般人群高。城市高于农村。主要表现：情绪低落，兴趣减退，活动减少疾病其他表现：食欲减退，失眠，早醒；思维活动变慢，不能集中注意力；容易疲劳， 做事特别犹豫不决；无价值感，过分自责，观念情绪低落兴趣减退容易疲劳无价值感过分自责精力明显减迟精神运动性迟滞或激越体重明显减轻或增加联想困难自觉思考能力显著下降明显减退反复出现想死的念头自我评价过低或有行为十字高架迷宫强迫游泳诊断标准CCMD-3(双相情感障碍抑郁发

2、作，抑郁症，心境恶劣)ICD-10 (国际疾病分类标准编码)DSM-IV 重性抑郁（major depression），双相障碍(bipolar disorder) 型,型 ，心境恶劣DSM-IV 重性抑郁症的诊断标准A.有情绪低落或/和兴趣、愉丧失。并出现下述至少4个症状，持续时间至少2周。躯体疾病或情感不协调的幻觉或妄想引起的除外。(1)大部分时间或几乎每天都有情绪低落。可以表现为主动诉说悲伤或空虚感，或旁人观察到流泪等现象。注意：儿童或青少年可以表现为容易激惹。(2）大部分时间，几乎在所有活动都表现出兴趣减退或愉可以是自己主诉，也可来自他人观察。缺乏。(3) 并非由于节食而引起的体重减轻

3、，或体重增加，如一个月内体重变化超过5%；或几乎每天的食欲都减少。注意：在儿童也要考虑没有出现期待的体重增加的情况。(4) 几乎每天都有失眠或睡眠过度。DSM-IV 重性抑郁症的诊断标准(5)几乎每天都有精神运动性迟滞或容易激惹。应该被他人观察到，而不仅仅是主观感觉到不平静或动作慢。(6)几乎每天都感觉疲劳或精力不够。(7)几乎每天都有无用感；或不适当的感，甚至达到妄想程度。不应该仅仅是因为患病而自责。(8) 几乎每天都不能思考、集中注意力或做决定。可以是主观感觉，也可来自他人观察。(9) 反复想到死亡，不包括对死亡的害怕；反复出现无具体计划的死亡意念；或有划。企图；或已有计DSM-IV 重性

4、抑郁症的诊断标准B. 这些症状不满足混合发作的标准。C. 这些症状给本人带来不便，并且损害了社会交往、职业或其他重要能力。D. 这些症状不是由物质如甲状腺功能减退。、药物或躯体疾病引起，E. 这些症状不能用丧失亲密的人来解释，如失去爱人后这些症状持续已经超过2个月，其特点为显著的功能缺损、地沉湎于生活无价值、意念、精神病性症状、或精神运动性迟缓。边缘系统：前额叶、海马旁回，海马、齿状回、扣带回、杏仁核、丘脑前核、下丘脑等病因发病机理遗传因素生物胺假说生物因素多基因遗传假说社会心理因素内分泌假说双相型患者，一级亲属（兄抑郁是对照组2-10倍生物因素女等）患重性重性抑郁患者，一级亲属患该病的几率是

5、对照组的2-3倍二级亲属（舅姑等）患病几率比一级低，比对照高多数寄养研究发现，重性抑郁有遗传倾向。抑郁症父母所生的寄养子中患病率高于正常父母所生的寄 养子。孪生子研究：单卵双生子重性抑郁障碍同病率50%，双卵双生子的重性抑郁同病率是10-25%。二级亲属（舅姑等）患病几率比一级低，比对照高单胺能递质代谢、转运、调节等相关基因：5HT受体、转运体(5HTT)、NE转运体、色胺酸羟化酶（TPH）、单胺氧化酶A（MAOA）.11p15 , (编码Tyrosine hydroxylase, Dopamine receptor D4,Tryptophane hydroxylase的基因) ,11q222

6、3(Dopamine receptor D2),18q2123, 21q22.3, Xq2528.单胺假说抑郁症的发生与脑内5HT等儿茶酚胺的缺乏有关。5-羟色胺5-HT再摄取抑制剂治疗抑郁症有效5-HT耗竭可使抑郁症状恶化者血液，尿和脑脊液5-HT代谢物浓度抑郁症患者及部分异常。脑内主要单胺类递质投射系统At least 15 types and subtypesMultiple transduction mechanisms 5HT-1A: role in anxiety/depression 5HT-1D: role in migraine5HT-2: role in CNS vario

7、us behaviors, and in cardiovascular system5-HT3: role in nausea and vomiting esp. due to Chemotherapy.抑郁症的发生与脑内应激机制过度激活有关。K. Erickson et al. Neuroscience and Biobehavioral Reviews 2003 抑郁症中情绪的感知、记忆和体验的神经生物学系统药物治疗SSRI ：如氟西汀，帕乐西汀，舍曲林5-HT2拮抗剂 ： 奈法唑酮，5-HT1A激动剂伊沙匹隆三环类：如阿米替林，氯丙米嗪，多虑平其他：博乐欣，布普品, 达体朗非药物治疗人际

8、间心理治疗认知行为治疗婚姻家庭治疗光治疗精神分裂症SchizophreniaPhrenia(心理)Schiz(分离)精神医生优金伯尔乐 把心理分裂 ,“人格1911,失去了完整性”“在我的个性中,一幅整合性的心理画卷被撕开,破碎成一小块,一小块, 弄得我像一个摇晃不止的汉堡包无止境地分散在宇宙中. ”（ Mendel,1976 ）精神癌症。The Starry NightJohn Forbes NashLouis WainVincent Willem van GoghSchizophrenia is a chronic and debilitating disorder with a life

9、time prevalence near 1%.Schizophrenia affects about 24 million people worldwide.Schizophrenia is a treatable disorder, treatment being more effective in its initial stages.More than 50% of persons with schizophrenia are not receiving appropriate care.90% of people with untreated schizophrenia are in

10、 developing countries.四A“基本症状 Apathy情感淡漠 Associative Loseness联想障碍 Abulia Autism意志缺乏内向性ICD-10,全称为“The International Statistical Classificationof Diseases and Related Health Problems 10th Revision (ICD-10)”，即国际疾病伤害及死因分类标准第十版第五章精神和行为障碍诊断标准（国际标准）DSM-IV,The Diagnostic and Statistical Manual of Mental Dis

11、orders，简称DSM精神疾病诊断与统计手册（美国标准）CCMD-3,中国精神疾病分类与诊断标准第3版（中国标准）DSMIV main diagnostic categories of psychotic disordersCCMD-3精神疾病诊断标准1、症状标准2、严重标准3、病程标准4、排除标准Diagnostic criteria (CCMD-3)症状标准 至少有下列2项，单纯型分裂症加规定：1 反复出现的言语性幻听；2 明显的思维松弛、思维破裂、言语不连贯，或思维贫乏或思维内容贫乏；3 思想入、被撤走、被播散、思维中断，或强制性思维；4 被动、被控制，或被洞悉体验；5 原发性妄想（包

12、括妄想知觉，妄想心境）或其他荒谬的妄想；6 思维逻辑倒错、病理性象征性思维，或语词新作；7 情感倒错，或明显的情感淡漠；8 紧张综合征、怪异行为，或愚蠢行为；9 明显的意志减退或缺乏。病程标准1 符合病症标准和严重标准至少已持续1个月，单纯型另有规定。2 若同时符合分裂症和情感性精神障碍的症状标准，当情感症状减轻到不能满足情感性精神障碍症状标准时，分裂症状需继续满足分裂症的症状标准至少2周以上，方可诊断为分裂症。排除标准1 器质性精神障碍（脑质性及躯体疾病所致）2 精神活性物质所致精神障碍3 非成瘾物质所致精神障碍妄想 (delusions) 病理性歪曲的信念妄想：关系(牵联观念)、被害、影响

13、、嫉妒、钟情、夸大妄想等身体妄想妄想关系妄想控制妄想夸大妄想非血统妄想幻觉(hallucinations)：没有客观刺激作用于感觉器官，出现的知觉体验。幻听(auditory hallucination) 肯定的、幻 视 （visual hallucination） 幻嗅（olfactory hallucination）幻味（gustatory hallucination）幻触（tactile hallucination）的、命令性的disordered thoughts范围：散漫内容：无逻辑必然联系结构：不严谨主题：不易理解思维散漫内容：无逻辑性结构：句子语法正确，缺联系主题：无主题，不理解

14、疾病：精神分裂症思维破裂内容：支离破碎结构：词与词无联系主题：无主题疾病：严重意识障碍象征性思维 主要为紧张症木僵动作和行为明显减少。违拗症对外来要求不由自主的抗拒。刻板症病人无意识地、重复地做一些简单的动作。 常伴有躯体异常表现，如肢端冰凉，低血压等。意思清晰。情感平淡(apathy)缺乏与人交流的动机而非能力。精神动力学认为是一种过度压抑机制。言语缺乏（reduction in spontaneous speech） 少言，给他人带来受挫感行为动机缺乏（lack of motivation）。自知力一般受损，绝大多数病人不认为自己有而坚信有人恶意加害于他。体验，大多有意识障碍，定向力、智力

15、活动良好。其妄想、幻觉都是在意识清晰下出现的不主动求医、拒绝治疗、治疗依从性差.研究的角度I型VS.II型临床角度偏执型(paranoid schizophrenia)紧张型(catatonic schizophrenia)青春型 (hebephrenic schizophrenia)，瓦解型单纯型 (Simple schizophrenia)未分化型I/II型分类 (1980年由英国学者Crow提出)型精神分裂症的特点型精神分裂症的特点n 急性起病n 阳性症状n 缓解后社会功能良好n 对药物治疗反应良好n 多巴胺功能亢进症状为主预后不良对药物治疗反应不佳无多巴胺功能亢进的证据病前适应不良，起

16、病年龄较早有脑结构异常大多数病人为一种混合类型与某些神经症的区别：有无自知力，感不感到痛苦， 是精分症与所有神经症的区分之要点。与偏执狂的区别：偏执狂以高度系统妄想为主要症状 ，别 的方面基本正常，病人可以很好地完成工作，社会适应能力保存，常不就诊。GeneticsBiologicalParental ageDrug abuseRisk factorsUrbanSocialMigration因遗传):同卵双生子的17%。未患精神分裂症的很高。一般人群患病率（1%） 得多， 其子女为13% ， 孙。遗传研究 (多基生子的共患率为患病的可能性共患率为48%,异卵双同卵双生子其子女家庭研究:的患病率

17、要高 环境因素的作用，精神分裂症的家属子女为6% 不能排除1970年以来，CT、MRI、PET等技术用于精神分裂症的研究，发现精神分裂症患者并非“功能性”精神病，脑部存在异常。CT发现有部分病人有脑室（尤其是侧脑室和第三脑室）扩大和脑皮质萎缩。MRI研究除肯定CT的发现外还发现脑皮质、额部和小脑结构较小，且发现脑容积的减少主要发生在灰质。PET研究发现精神分裂症患者出现幻听时，丘脑投射区有激活现象，表明病人丘脑的感觉滤过作用受到损害。正常人在进行心理测试时，前额叶、丘脑、小脑均被激活，而精神分裂症患者无激活现象。Potential pharmacologic interventions to

18、treatschizophreniaSchematic representation of the synaptic circuitry rele vant to the pathophysiology of schizophrenia发病机理多巴胺假说5-TH假说谷氨酸假说5-羟色胺（5-HT）假说精神分裂症患者在急性期血液、脑脊液中的5-HT含量偏低，随着精神症状的改善和病情好转，5-HT的含量逐渐恢复正常。近年来随着新型抗精神病药物如氯氮平、维思通、奥兰扎平、思瑞康等精神药理特性的深入研究，意识到5-HT2A受体可能与精神分裂症的幻觉妄想有关。Others non-dopaminergi

19、c systems and their corresponding therapysin schizophreniaGlutamate and NMDAreceptor hypofunctionu The N-methyl-D-aspartic acid receptor (NMDAR) hypofunction hypothesis developed from the finding that drugs which block glutamate NMDARs, such as phencyclidine (PCP), induce effects almost identical to

20、 the positive and negative symptoms seen in schizophrenia.u Animals given chronic doses of NMDAR antagonists developed loss of grey matter similarly reported in schizophrenia, while a relative deficit in NMDAR binding has been found in the left hippocampus of schizophrenic patients usingSPECT imagin

21、g.-Aminobutyric acid (GABA)Patients with schizophrenia have evidence of reduced GABAergicneurotransmission in the prefrontal cortex.Drugs enhancing GABAergic function would be expected tobe useful by reducing excessive cortical glutamate release.GlycineGlycine is an amino acid that is inhibitory in

22、the spinal cord and brain stem but also acts as a co-agonist at glutamate NMDARs. Genetic and pharmacologically- induced deficiencies in glycine binding in mice produce behavioral changes that model the negative and cognitive symptoms of schizophrenia. Several studies have tested the effects of comb

23、ining glycine with certain antipsychotics or usingglycine transport inhibitors with promising results.Glycine and Gly-T1 transport inhibitors in order to enhance NMDAR-mediatedneurotransmission for the treatment of schizophrenia.D-SerineD-Serine is the main NMDAR co-agonist and it potentiates NMDAR

24、function. Daily administration of large quantities of D-serine alone or as an adjunct to atypical antipsychotics has been reported to improve schizophrenic symptoms. D- Serine is metabolized by D-amino acid oxidase (DAO) and inactivation of DAO in mice has been reported to improve behavioral deficit

25、s which are similar to thenegative and cognitive symptoms in schizophrenia.Some DAO inhibitors currently under study show increased D-serine bioavailabilitywhen co-administered with D-serine, allowing for the administration of a lowerdose of D-serine to patients in treatmentNicotinic receptorsPostmo

26、rtem studies with schizophrenic patients have found abnormalities in the alpha-7 nicotinic receptor subtype expression, and a gene locusharboring the alpha-7 nicotinic receptor has been linked with schizophrenia.Animal studies suggest that nicotine transiently normalizes similar sensory gating defic

27、its as seen in schizophrenia (manifesting as an inability to appropriately pay attention to sensory stimuli).Adouble blind, placebo- controlled trial of galantamine, a combined cholinesterase inhibitor and allosteric potentiator of nicotinic receptors, was found to enhance cognition. Atrial of a sel

28、ective alpha-7 agonist has also shown cognitive enhancementin schizophrenia.Muscarinic(毒蕈碱)receptorsu Apostmortem study with schizophrenic patients has found reduced levels of muscarinic receptors in the caudate-putamen. Non-medicated schizophrenic patients were found to have reduced muscarinic rece

29、ptor availability on SPET imaging. Furthermore, clozapine clearly acts as a partial agonist at the muscarinic M1 and M4 receptors, and its affinity for these receptors is several-fold higher than for the dopamine D2 receptor.u Therefore, muscarinic partial agonists might be potential therapeutic age

30、nts in schizophrenia, as well as add-on treatments to improve the efficacy of atypicalantipsychotics. Some preclinical evidence exists supporting this hypothesis.Nitric oxide (NO) and arginineInterfering with NO production in rodents has been reported to reverse PCP- induced effects, However, there

31、is also evidence from animal studies with PCP that the underproduction of NO may be linked with schizophrenia, Postmortem studies have identified disrupted cellular migration and functioning involving NO- producing neurons in schizophrenia, supporting the neurodevelopmental theory and suggesting that a decrease in the production of NO in cortical areas could perhaps contribute to altered neuronal development, disrupted circuitry, hypofronta