SCHIZOPHRENIA Zhang, Bin Institute of Pharmacology School of Medicine Shandong University

Psychotic Disorders (精神失常) Schizophrenia (精神分裂症) Mania (躁狂症) Depression (抑郁症) Anxiety (焦虑症) WHO 10月10日--世界精神卫生日

Neuropathy Psychopathy （神经病） （精神病） ≠ 神经病：指神经系统发生的器质性疾病，一般都有神经组织结构的改变。主要表现是神经功能损害，如意识障碍、失语、瘫痪、抽搐、震颤、麻木、疼痛、大小便障碍、动作不稳、感觉减退或消失等。 精神病：是大脑高级神经活动严重障碍的疾病，常表现为认知、情感、意志和行为的反常。有两大类：功能性精神病（原发性）及器质性精神病（继发性）。 Neuropathy Psychopathy （神经病） （精神病） ≠

病例1 Schizophrenia(精神分裂症) 某男，42岁，一年前生意失败，回父母家居住。半年前的一个深夜，患者发现对面楼里的灯光刺眼的照进自己的房间。此后渐发现邻居常“话里有话”，内容多涉及患者隐私，开始怀疑自己的房间被人录音、摄像。三月前，患者听到脑子里有个自称“国家安全部少校”的人同自己讲话，声称他是“全国一号嫌犯”。后又出现一自称“老书记”的女声为他辩解。“少校”、“书记”间意见针锋相对，令患者不胜其烦。半月前，患者多次走访各政府部门，要求“澄清事实”，并计划给世界各大报刊写信，申诉自己“受人迫害”的经历。

病例2 Mania (躁狂症) 某女，19岁，近两周来情绪异常愉悦，整天兴高采烈，忙东忙西，自我感觉良好，喜欢逛街购物，乱花钱，打扮花哨一改以往。话多，滔滔不绝。精力旺盛，晚上忙碌到后半夜。进入病房后毫不当成住院，说是来疗养的。蹦蹦跳跳地跑来跑去，很热情的与医生、护士打招呼。说话幽默，不时引起其他围观病友哈哈大笑。

病例3 Depression (抑郁症) 某女，30岁，三个月来，木讷，话少，活动也较前减少，不愿意出门，在家唉声叹气，有时独自流泪，家人问及时偶尔低声回答，说脑子没用了，想事情想不出来，病治不好了，自己做错了事，有罪，该死。以前喜欢看的电视剧也不感兴趣了。称胃口差，每天只吃一顿，体重明显下降，睡眠减少，早上3、4点钟就醒来。就诊时，由家人搀扶，低着头，问多少答，声音低而缓慢，或点头、摇头示意。谈到病情时，流着泪说：“我该死，我不该拿国家的钱，我应该死”。

病例4 Anxiety (焦虑症) 王**，女，30岁，一年前坐公交时因人多拥挤而出现心慌胸闷呼吸困难，以后每次上公交无论人多人少，都有这种感觉，以至不敢再乘车，发展到去商场广场，只要自己感觉人多就会发病。

Schizophrenia (精神分裂症) Symptoms Aetiology Neurobiology Treatment prognosis

Symptoms Formal thought disorder (形式思维障碍) Emotional disorders (情感障碍) Motor, volitional and behavioural disorders (意志行为障碍) Abnormal perceptions (知觉异常) Abnormal ideas (思维内容障碍） Lack of insight (自知力缺陷）

Formal thought disorder (形式思维障碍) 思维联想过程缺乏连贯性和逻辑性 思维松弛 思维破裂 语词新作 思维中断 强制性思维

Emotional disorders (情感障碍) 患者对周围事物情感反应缺失或不协调 情感淡漠 情感与周围环境不协调

Motor, volitional and behavioural disorders （意志行为障碍） 孤僻离群、被动退缩、缺乏主动性，无所事事，生活懒散，意志减退，工作学习没有兴趣，能力明显下降，社会功能受损。还可出现愚蠢、幼稚、怪异行为。 刻板症 (Stereotypy) 装相 (Mannerisms) 紧张症 (Catatonia) 木僵症，蜡样屈曲 ( Catalepsy, waxy flexibility) 兴奋冲动、行为杂乱 (如破坏性行为、暴力、裸奔)

Abnormal perceptions (知觉异常) hallucinations：指客观现实中并不存在某种事物的情况下，患者却感知到他的存在。 幻听 (Auditory hallucinations) 幻视 (Visual hallucinations) 幻嗅 (Olfactory hallucinations) 幻味 (Gustatory hallucinations)

Abnormal ideas （思维内容障碍） delusion：一种病理性的歪曲信念，这种信念与客观事实等不符，甚至荒谬离奇，但患者坚信不疑，无法被说服。 关系妄想 (delusions of reference) 被害妄想 (delusions of persecution) 夸大妄想 (grandiose delusions) 疑病妄想 (hypochondriacal delusions) 妄想心境 (delusional mood)

Classification of schizophrenia TypeⅠ (Positive symptoms): existence of an abnormal phenomenon delusion, hallucination, thought disorder, bizarre behaviour, catatonia (紧张症), etc. TypeⅡ (Negative symptoms): absence or diminution of normal function and reactions affective apathy, social withdrawal, poor initiative and motivation, etc.

Aetiology Genetic aspects: Somato-biological factors: correlated with the degree of genetic relatedness Somato-biological factors: after viral epidemics winter months obstetric complications Social enviroment factors: “schizophrenogenic mother” bad life events economic status character

堂表兄弟姐妹 侄子外甥 异父同胞 同胞 异卵双生

Neurobiology Pathomorphology research Biochemistry metabolism research The molecular basis for schizophrenia concerns with the abnormalities of some neurotransmitter function, especially dopamine.

Neurotransmitters of schizophrenia Dopamine (DA) 5-hydroxytryptamine (5-HT) …

Mesocortical and Mesolimbic DA system activity ↑ Dopamine theory Mesocortical and Mesolimbic DA system activity ↑ (D2样受体数目增加，但DA及其代谢产物并无增加)

1. Nigrosubstantia-striatal DA system: Regulate extrapyramidal function 2. Mesocortical DA system 3. Mesolimbic DA system Regulate cognition, thinking, emotion, feeling 4. Tubero-infundibular DA system Regulate pituitary hormone release

The Subtypes of DA Receptor D1，D2，D3，D4，D5 subtypes DA receptor classified D1-like receptors: D1 and D5 D2-like receptors: D2, D3, D4

Most antipsychotic drugs are the antagonist of D2-like receptor Nigro-striatal system： D1-like receptors D2-like receptors (D2 、D3) Mesocortical and mesolimbic system: D2-like receptors (D2、D3、D4) Tubero-infundibular D2-like receptors (D2) Most antipsychotic drugs are the antagonist of D2-like receptor

Treatment Antipsychotic drugs Psychosocial intervention (社会心理干预) Electric shock therapy

Antipsychotic agents (Neuroleptics)

The Mechanisms of Antipsychotic Drugs 1. Block D2 –like receptor in the mesolimbic and mesocortical pathways. 2. Block 5-HT receptor

Classification of antipsychotic drugs Phenothiazines (吩噻嗪类) chlorpromazine (氯丙嗪) 2. Thioxanthenes (硫杂蒽类) chlorprothixene (氯普噻吨) 3. Butyrophenones (丁酰苯类) haloperidol (氟哌啶醇), droperidol (氟哌利多) 4. others penfluridol (五氟利多), sulpiride (舒必利), clozapine (氯氮平), risperidone (利培酮) olanzapine (奥氮平

Chlorpromazine （氯丙嗪，wintermine, 冬眠灵）

Pharmacological Effects Central nervous system Blocking DA-R Autonomic nervous system Blocking α-R and M-R Endocrine system

Central nervous system Antipsychotic effects Antiemetic effects Effects of temperature regulation

（1）Antipsychotic effect： neuroleptic effect normal persons: sedative effect, easy to induce sleep schizophrenia patients: ---- control excited state of agitation, stabilize emotion ---- large dose continuous treatment : eliminate hallucinations and delusions ---- ineffective on depression, even exacerbated Mechanism: Block D2 like receptor in mesolimbic and mesocortical pathways.

(2) Antiemetic action(镇吐作用) effective on vomiting caused by some reasons, but no effect on vomiting caused by vestibular stimulation mechanisms: low dose: blocks D2 receptor of CTZ large dose: directly inhibit the vomiting center effective on intractable hiccups (顽固性呃逆) Inhibit hiccups regulating center

body temperature changed dependent on environment temperature (3) Effect on temperature regulation body temperature changed dependent on environment temperature reducing body temperature is not only in fever patients, but also in normal individuals different from NSAIDs Mechanisms: Inhibit thermoregulatory center in hypothalamus, cause the failure of temperature regulation

Autonomic nervous system(1) Blocking α-R vessel dilation Peripheral resistance ↓ Orthostatic hypotension Heart rate ↑

Autonomic nervous system(2) Blocking M-R Paralysis of accommodation Dry mouth Difficulty urinating Constipation Uroschesis Paralytic ileus …… 尿潴留 麻痹性肠梗阻 ……

Endocrine system Prolactin release-inhibiting factor (PIF) ↓ PRL↑ Amenorrhea-galactorrhea Infertility Gonadotropin-release hormone (GnRH)↓ FSH,LH↓ Delayed ovulation Corticotropin (ACTH)↓ glucocorticoid↓ Growth hormone(GH)↓ treat Giantism Inhibit D2 –R in tubero-infundibular pathway

Clinical Application Hypothermia anesthesia ＆ Artificial hibernation Schizophrenia Vomiting ＆ Intractable hiccups Hypothermia anesthesia ＆ Artificial hibernation

1. Schizophrenia particularly acute and has a significant positive symptoms (Ⅰ type) the manic episode in bipolar affective disorder ineffective for type Ⅱ patients or even worse

2. Vomiting and Intractable hiccups strong antiemetic (止吐剂) marked curative effect in intractable hiccups. No effect on vomiting caused by vestibular stimulation (motion sickness)

3. Hypothermia anesthesia and Artificial hibernation chlorpromazine deep sleep Lytic cocktail dolantin temperature↓ promethazine basal metabolism↓ tolerance↑ Artificial hibernation reaction↓ serious trauma Indication hyperpyrexia septic shock hyperthyroidism crisis … with the help of physical cooling

人工冬眠的方法是将氯丙嗪和异丙嗪两种药物等量混合，按每公斤体重1毫克的剂量加入输液小壶中静脉滴入，半小时后如呼吸和脉搏都平稳，可用同等剂量肌肉注射一次，这时患儿即可进入沉睡状态。患儿入睡后在腹股沟、腋下放上冰袋，躯干部可用低于体温2℃～3℃的水做温湿敷。如果患儿出现寒战、紫绀和烦躁等寒冷反应，说明冬眠药作用不够，应该撤去冰袋和温湿敷，增加冬眠药物，然后再用冰袋等物理降温。 应用冬眠疗法后，患儿无寒冷反应，耐受良好，体温逐渐下降，说明诱导成功，然后开始进入维持阶段。维持阶段每2～4小时注射一次冬眠混合剂，最好将药物加入输液小壶中滴入，避免肌肉注射时疼痛惊醒患儿。使患儿维持在冬眠状态，体温维持在33 or 34℃～35℃之间。低温维持时间一般以16～24小时为宜，必要时可适当延长，但不要超过3天，以免副作用过多。待患儿病情稳定后，停止冬眠给药，并逐渐撤去冰袋，使体温逐渐恢复到正常，患儿逐渐清醒。

Question What is the difference between NSAIDs and chlorpromazine in body temperature regulation ?

NSAIDs 氯丙嗪 比较NSAIDs与氯丙嗪对体温的影响 机制 抑制COX, 抑制下丘脑体温 减少PGs生成 调节中枢 作用特点 降低高热体温， 使体温随环境温 不降低正常体温 度变化 应用 炎性发热 人工冬眠

Comparison between NSAIDs and Chlorpromazine NSAIDs Chlorpromazine Mechanism inhibit COX in inhibit thermoregulator CNS → PGs↓ make it out of function Effect set point ↓ BT alters with the BT ↓ environmental temperature Clinical uses fever artificial hibernation rheumatic fever

Adverse reactions 1. Common adverse reactions (2) M-R Blockade (1) CNS inhibition (2) M-R Blockade (3) α-R Blockade

2. Extrapyramidal reactions (1) Parkinson’s syndrome (2) Akathisia (静坐不能) (3) Acute dystonia (急性肌张力障碍): facial grimacing (做鬼脸) torticollis (斜颈) respiratory dyskinesia (呼吸运动障碍) dysphagia (吞咽困难) (4) Tardive dyskinesia: sucking and licking of the lips (吸吮、舔舌、咀嚼三联征) abnormal choreoathetoid movements (舞蹈手足徐动症)

block D2-like receptor of Nigro-striatal system, （1）～（3）： mechanism: block D2-like receptor of Nigro-striatal system, weaken DA function, enhance Ach function treatments: central anticholinergic drugs eg. trihexyphenidyl (苯海索) scopolamine(东莨菪碱)

change to clozapine (氯氮平) （4）： mechanism: long-term block DA-R supersensitivity of DA-R or feedback to increase the release of presynaptic DA treatments: change to clozapine (氯氮平)

3. Neuroleptic malignant syndrome (NMS, 神经阻滞药恶性综合征) Idiosyncratic response Syndrome: hyperthermia, hypertension, muscular rigidity, disorders of consciousness, etc. Treatment: Dantrolene (丹曲林) Dopaminergic agonists (bromocriptine) Cooling

4. Drug-induced psychosis 5. Convulsion and epilepsy 6. Allergic reactions 7. Cardiovascular and Endocrine system 8. Acute intoxication drowsiness, BP drop to shock levels, myocardial damage ( tachycardia, abnormal ECG ) symptomatic treatment, but not with adrenaline

chlorprothixene(氯普噻吨, tardan, 泰尔登) 1. weaker effect on hallucinations and delusions than chlorpromazine 2. have anti-anxiety and anti-depressant effect 3. used for schizophrenia with anxiety and depression; anxiety neurosis (焦虑性神经官能症); involutional depression (更年期抑郁症)

Haloperidol（氟哌啶醇） 1. strong antipsychotic effects 2. severe extrapyramidal reaction weak effect on cardiovascular system 3. depression is contraindication

Droperidol（氟哌利多） Neuroleptanalgesia（神经阻滞镇痛术）： droperidol + fentanyl (芬太尼) used for minor surgery, premedication, control aggressive behavior of psychopathy

IV. Other Antipsychotic Drugs Penfluridol (五氟利多) Sulpiride(舒必利) Clozapine(氯氮平) Risperidone(利培酮)

Clozapine (氯氮平) 1. atypical antipsychotic agent: high affinity for D4-R and 5-HT2A-R (serotonin-dopamine antagonist, SDA) 2. broad spectrum: type Ⅰ and type Ⅱ acute and chronic 3. used for tardive dyskinesia (迟发型运动障碍) 4. almost no extrapyramidal reaction 5. cause agranulocytosis

氯丙嗪与氯氮平的比较 作用机制： 氯丙嗪 阻断 D2 样受体 氯氮平 阻断 D4受体 中脑－边缘通路 中脑－皮层通路 黑质－纹状体通路 结节-漏斗通路 中脑－边缘通路 中脑－皮层通路

Risperidone (利培酮,维思通) 1. atypical antipsychotic drug block 5-HT2 and D2 receptor（5-HTD2） 2. broad spectrum： type Ⅰand type Ⅱ acute and chronic 3. effective at small dose, rapid onset 4. few adverse reactions, better compliance (依从性) than others.

Sulpiride (舒必利) 1. good effectiveness, rapid onset, drug electric shock 2. have antidepressant efficacy, effective for refractory cases 3. selectively block D2 -R of meso-limbic system, slight extrapyramidal reaction 4. Mania is contraindication

药物选择 ① 非典型抗精神病药物作为一线药物 ② 典型抗精神病药物作为二线药物 ③ 长效药物主要用于服药依从性不好的患者 治疗疗程 ①急性期：足量药物，至少4-6周 ②恢复期(巩固期)：使用原有效药物和剂量继续治疗，至少3-6月 ③维持期(康复期)：根据个体病情确定维持剂量，疗程不少于2-5年

Prognosis 预后良好的因素包括：病前性格开朗，社会适应能力良好，急性起病，病程短，发病前存在明显的心理社会应激或躯体疾病，发病年龄晚，精神分裂症核心症状不典型，且具有鲜明的情感色彩，获得早期治疗，治疗效果好，无反复发作史，家庭和社会支持系统好，无精神疾病家族史。反之预后不佳。

下课了！