1、神經(jīng)精神疾病張 智2013.11.7抑郁癥患病率國內(nèi)約4%，國外10%，年患病率10.3%。疾病醫(yī)療負擔排名：抑郁癥占第1位 (中國)人群分布：女：男=2：1，在人際關(guān)系不良，獨居，離婚者中比一般人群高。城市高于農(nóng)村。主要表現(xiàn)：情緒低落，興趣減退，活動減少疾病其他表現(xiàn)：食欲減退，失眠，早醒；思維活動變慢，不能集中注意力；容易疲勞， 做事特別猶豫不決；無價值感，過分自責(zé)，觀念情緒低落興趣減退容易疲勞無價值感過分自責(zé)精力明顯減遲精神運動性遲滯或激越體重明顯減輕或增加聯(lián)想困難自覺思考能力顯著下降明顯減退反復(fù)出現(xiàn)想死的念頭自我評價過低或有行為十字高架迷宮強迫游泳診斷標準CCMD-3(雙相情感障礙抑郁發(fā)

2、作，抑郁癥，心境惡劣)ICD-10 (國際疾病分類標準編碼)DSM-IV 重性抑郁（major depression），雙相障礙(bipolar disorder) 型,型 ，心境惡劣DSM-IV 重性抑郁癥的診斷標準A.有情緒低落或/和興趣、愉喪失。并出現(xiàn)下述至少4個癥狀，持續(xù)時間至少2周。軀體疾病或情感不協(xié)調(diào)的幻覺或妄想引起的除外。(1)大部分時間或幾乎每天都有情緒低落?？梢员憩F(xiàn)為主動訴說悲傷或空虛感，或旁人觀察到流淚等現(xiàn)象。注意：兒童或青少年可以表現(xiàn)為容易激惹。(2）大部分時間，幾乎在所有活動都表現(xiàn)出興趣減退或愉可以是自己主訴，也可來自他人觀察。缺乏。(3) 并非由于節(jié)食而引起的體重減輕

3、，或體重增加，如一個月內(nèi)體重變化超過5%；或幾乎每天的食欲都減少。注意：在兒童也要考慮沒有出現(xiàn)期待的體重增加的情況。(4) 幾乎每天都有失眠或睡眠過度。DSM-IV 重性抑郁癥的診斷標準(5)幾乎每天都有精神運動性遲滯或容易激惹。應(yīng)該被他人觀察到，而不僅僅是主觀感覺到不平靜或動作慢。(6)幾乎每天都感覺疲勞或精力不夠。(7)幾乎每天都有無用感；或不適當?shù)母?，甚至達到妄想程度。不應(yīng)該僅僅是因為患病而自責(zé)。(8) 幾乎每天都不能思考、集中注意力或做決定?？梢允侵饔^感覺，也可來自他人觀察。(9) 反復(fù)想到死亡，不包括對死亡的害怕；反復(fù)出現(xiàn)無具體計劃的死亡意念；或有劃。企圖；或已有計DSM-IV 重性

4、抑郁癥的診斷標準B. 這些癥狀不滿足混合發(fā)作的標準。C. 這些癥狀給本人帶來不便，并且損害了社會交往、職業(yè)或其他重要能力。D. 這些癥狀不是由物質(zhì)如甲狀腺功能減退。、藥物或軀體疾病引起，E. 這些癥狀不能用喪失親密的人來解釋，如失去愛人后這些癥狀持續(xù)已經(jīng)超過2個月，其特點為顯著的功能缺損、地沉湎于生活無價值、意念、精神病性癥狀、或精神運動性遲緩。邊緣系統(tǒng)：前額葉、海馬旁回，海馬、齒狀回、扣帶回、杏仁核、丘腦前核、下丘腦等病因發(fā)病機理遺傳因素生物胺假說生物因素多基因遺傳假說社會心理因素內(nèi)分泌假說雙相型患者，一級親屬（兄抑郁是對照組2-10倍生物因素女等）患重性重性抑郁患者，一級親屬患該病的幾率是

5、對照組的2-3倍二級親屬（舅姑等）患病幾率比一級低，比對照高多數(shù)寄養(yǎng)研究發(fā)現(xiàn)，重性抑郁有遺傳傾向。抑郁癥父母所生的寄養(yǎng)子中患病率高于正常父母所生的寄 養(yǎng)子。孿生子研究：單卵雙生子重性抑郁障礙同病率50%，雙卵雙生子的重性抑郁同病率是10-25%。二級親屬（舅姑等）患病幾率比一級低，比對照高單胺能遞質(zhì)代謝、轉(zhuǎn)運、調(diào)節(jié)等相關(guān)基因：5HT受體、轉(zhuǎn)運體(5HTT)、NE轉(zhuǎn)運體、色胺酸羥化酶（TPH）、單胺氧化酶A（MAOA）.11p15 , (編碼Tyrosine hydroxylase, Dopamine receptor D4,Tryptophane hydroxylase的基因) ,11q222

6、3(Dopamine receptor D2),18q2123, 21q22.3, Xq2528.單胺假說抑郁癥的發(fā)生與腦內(nèi)5HT等兒茶酚胺的缺乏有關(guān)。5-羥色胺5-HT再攝取抑制劑治療抑郁癥有效5-HT耗竭可使抑郁癥狀惡化者血液，尿和腦脊液5-HT代謝物濃度抑郁癥患者及部分異常。腦內(nèi)主要單胺類遞質(zhì)投射系統(tǒng)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.抑郁癥的發(fā)生與腦內(nèi)應(yīng)激機制過度激活有關(guān)。K. Erickson et al. Neuroscience and Biobehavioral Reviews 2003 抑郁癥中情緒的感知、記憶和體驗的神經(jīng)生物學(xué)系統(tǒng)藥物治療SSRI ：如氟西汀，帕樂西汀，舍曲林5-HT2拮抗劑 ： 奈法唑酮，5-HT1A激動劑伊沙匹隆三環(huán)類：如阿米替林，氯丙米嗪，多慮平其他：博樂欣，布普品, 達體朗非藥物治療人際

8、間心理治療認知行為治療婚姻家庭治療光治療精神分裂癥SchizophreniaPhrenia(心理)Schiz(分離)精神醫(yī)生優(yōu)金伯爾樂 把心理分裂 ,“人格1911,失去了完整性”“在我的個性中,一幅整合性的心理畫卷被撕開,破碎成一小塊,一小塊, 弄得我像一個搖晃不止的漢堡包無止境地分散在宇宙中. ”（ Mendel,1976 ）精神癌癥。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“基本癥狀 Apathy情感淡漠 Associative Loseness聯(lián)想障礙 Abulia Autism意志缺乏內(nèi)向性ICD-10,全稱為“The International Statistical Classificationof Diseases and Related Health Problems 10th Revision (ICD-10)”，即國際疾病傷害及死因分類標準第十版第五章精神和行為障礙診斷標準（國際標準）DSM-IV,The Diagnostic and Statistical Manual of Mental Dis

11、orders，簡稱DSM精神疾病診斷與統(tǒng)計手冊（美國標準）CCMD-3,中國精神疾病分類與診斷標準第3版（中國標準）DSMIV main diagnostic categories of psychotic disordersCCMD-3精神疾病診斷標準1、癥狀標準2、嚴重標準3、病程標準4、排除標準Diagnostic criteria (CCMD-3)癥狀標準 至少有下列2項，單純型分裂癥加規(guī)定：1 反復(fù)出現(xiàn)的言語性幻聽；2 明顯的思維松弛、思維破裂、言語不連貫，或思維貧乏或思維內(nèi)容貧乏；3 思想入、被撤走、被播散、思維中斷，或強制性思維；4 被動、被控制，或被洞悉體驗；5 原發(fā)性妄想（包

12、括妄想知覺，妄想心境）或其他荒謬的妄想；6 思維邏輯倒錯、病理性象征性思維，或語詞新作；7 情感倒錯，或明顯的情感淡漠；8 緊張綜合征、怪異行為，或愚蠢行為；9 明顯的意志減退或缺乏。病程標準1 符合病癥標準和嚴重標準至少已持續(xù)1個月，單純型另有規(guī)定。2 若同時符合分裂癥和情感性精神障礙的癥狀標準，當情感癥狀減輕到不能滿足情感性精神障礙癥狀標準時，分裂癥狀需繼續(xù)滿足分裂癥的癥狀標準至少2周以上，方可診斷為分裂癥。排除標準1 器質(zhì)性精神障礙（腦質(zhì)性及軀體疾病所致）2 精神活性物質(zhì)所致精神障礙3 非成癮物質(zhì)所致精神障礙妄想 (delusions) 病理性歪曲的信念妄想：關(guān)系(牽聯(lián)觀念)、被害、影響

13、、嫉妒、鐘情、夸大妄想等身體妄想妄想關(guān)系妄想控制妄想夸大妄想非血統(tǒng)妄想幻覺(hallucinations)：沒有客觀刺激作用于感覺器官，出現(xiàn)的知覺體驗。幻聽(auditory hallucination) 肯定的、幻 視 （visual hallucination） 幻嗅（olfactory hallucination）幻味（gustatory hallucination）幻觸（tactile hallucination）的、命令性的disordered thoughts范圍：散漫內(nèi)容：無邏輯必然聯(lián)系結(jié)構(gòu)：不嚴謹主題：不易理解思維散漫內(nèi)容：無邏輯性結(jié)構(gòu)：句子語法正確，缺聯(lián)系主題：無主題，不理解

14、疾?。壕穹至寻Y思維破裂內(nèi)容：支離破碎結(jié)構(gòu)：詞與詞無聯(lián)系主題：無主題疾病：嚴重意識障礙象征性思維 主要為緊張癥木僵動作和行為明顯減少。違拗癥對外來要求不由自主的抗拒。刻板癥病人無意識地、重復(fù)地做一些簡單的動作。 常伴有軀體異常表現(xiàn)，如肢端冰涼，低血壓等。意思清晰。情感平淡(apathy)缺乏與人交流的動機而非能力。精神動力學(xué)認為是一種過度壓抑機制。言語缺乏（reduction in spontaneous speech） 少言，給他人帶來受挫感行為動機缺乏（lack of motivation）。自知力一般受損，絕大多數(shù)病人不認為自己有而堅信有人惡意加害于他。體驗，大多有意識障礙，定向力、智力

15、活動良好。其妄想、幻覺都是在意識清晰下出現(xiàn)的不主動求醫(yī)、拒絕治療、治療依從性差.研究的角度I型VS.II型臨床角度偏執(zhí)型(paranoid schizophrenia)緊張型(catatonic schizophrenia)青春型 (hebephrenic schizophrenia)，瓦解型單純型 (Simple schizophrenia)未分化型I/II型分類 (1980年由英國學(xué)者Crow提出)型精神分裂癥的特點型精神分裂癥的特點n 急性起病n 陽性癥狀n 緩解后社會功能良好n 對藥物治療反應(yīng)良好n 多巴胺功能亢進癥狀為主預(yù)后不良對藥物治療反應(yīng)不佳無多巴胺功能亢進的證據(jù)病前適應(yīng)不良，起

16、病年齡較早有腦結(jié)構(gòu)異常大多數(shù)病人為一種混合類型與某些神經(jīng)癥的區(qū)別：有無自知力，感不感到痛苦， 是精分癥與所有神經(jīng)癥的區(qū)分之要點。與偏執(zhí)狂的區(qū)別：偏執(zhí)狂以高度系統(tǒng)妄想為主要癥狀 ，別 的方面基本正常，病人可以很好地完成工作，社會適應(yīng)能力保存，常不就診。GeneticsBiologicalParental ageDrug abuseRisk factorsUrbanSocialMigration因遺傳):同卵雙生子的17%。未患精神分裂癥的很高。一般人群患病率（1%） 得多， 其子女為13% ， 孫。遺傳研究 (多基生子的共患率為患病的可能性共患率為48%,異卵雙同卵雙生子其子女家庭研究:的患病率

17、要高 環(huán)境因素的作用，精神分裂癥的家屬子女為6% 不能排除1970年以來，CT、MRI、PET等技術(shù)用于精神分裂癥的研究，發(fā)現(xiàn)精神分裂癥患者并非“功能性”精神病，腦部存在異常。CT發(fā)現(xiàn)有部分病人有腦室（尤其是側(cè)腦室和第三腦室）擴大和腦皮質(zhì)萎縮。MRI研究除肯定CT的發(fā)現(xiàn)外還發(fā)現(xiàn)腦皮質(zhì)、額部和小腦結(jié)構(gòu)較小，且發(fā)現(xiàn)腦容積的減少主要發(fā)生在灰質(zhì)。PET研究發(fā)現(xiàn)精神分裂癥患者出現(xiàn)幻聽時，丘腦投射區(qū)有激活現(xiàn)象，表明病人丘腦的感覺濾過作用受到損害。正常人在進行心理測試時，前額葉、丘腦、小腦均被激活，而精神分裂癥患者無激活現(xiàn)象。Potential pharmacologic interventions to

18、treatschizophreniaSchematic representation of the synaptic circuitry rele vant to the pathophysiology of schizophrenia發(fā)病機理多巴胺假說5-TH假說谷氨酸假說5-羥色胺（5-HT）假說精神分裂癥患者在急性期血液、腦脊液中的5-HT含量偏低，隨著精神癥狀的改善和病情好轉(zhuǎn)，5-HT的含量逐漸恢復(fù)正常。近年來隨著新型抗精神病藥物如氯氮平、維思通、奧蘭扎平、思瑞康等精神藥理特性的深入研究，意識到5-HT2A受體可能與精神分裂癥的幻覺妄想有關(guān)。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(毒蕈堿)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