Drugs Used to Treat Psychiatric Disorders

1. Drugs Used to Treat Psychiatric Disorders chenzhong@zju.edu.cn 医科研楼B402-416

2. 教学目标： 掌握：精神药物（抗精神病药、抗躁狂药、抗抑郁药）分类及其代表药；以氯丙嗪为代表，抗精神失常药的药理作用、临床应用和不良反应特点；抗抑郁药的分类、药理作用和临床应用,以丙米嗪(米帕明)为代表，抗抑郁药的药理作用和作用机制、临床应用。 了解：其他主要药物的特点。

3. Psychiatric Disorders • Lifetime prevalence: about 1/3- 1/2 of population • - Mood Disorder: 8-10% • - Anxiety Disorder: 15% • - Substance abuse: 16% • - Schizophrenia: 1% • - Eating disorders, somatoform disorders, and personality disorders • Antipsychotic agents • Antidepressant and antimanic agents • Axiolytics

4. Schizophrenia ----Schizophrenia, a particular kind of psychosis, is characterized by a thinking disturbance Neurological disorder - impaired ability to perceive, understand & interpret the environment Impaired social and occupational function Behavioral syndrome – predictable or not

5. Epidemiology Incidence consistent worldwide --1% general population --Hereditary trend: 10% siblings , parents / offspring, dizygotic twins 50% monozygotic twins Environmental factors implicated --Prenatal stress - infection, famine, war, death of spouse --Season of birth - winter > summer --Cannabis --Urban setting > rural setting Age of onset --Men 17 - 27, Women 17 - 37 --Childhood onset extremely rare: 1 in 10,000-100,000 Outcome --10% good - optimistic --80% remission without full recovery --10% no remission

6. Case Study • W.G, 19 years old, undergraduate, member of rowing team of school, was found staying by himself, avoiding the company of friends and skipping school and athletic training. Later, he was heard speaking to himself as he sat isolated in his room, mumbling and smiling. Then he confided to his roommate that he had uncovered a grand conspiracy to rob him of his athletic abilities and that he could hear the conspirator’s voices as they planed to destroy him. Finally, he accused his roommate of being a part of the conspiracy. • students

7. Signs & Symptoms 1. Positivesymptoms Delusions (妄想)- fixed false beliefs outside cultural norm (bizarre vs. non bizarre) Hallucinations (幻觉)- perceptual (usually auditory or visual, but sometimes tactile or olfactory), have no outside source “Like my voice” Not an illusion (错觉, a mistaken perception for which there is an actual external stimulus) Disorganization – pattern of speech/thought/behavior, making up words without a meaning (neologisms)

8. 2. Negativesymptoms Affective flattening (absence of emotional expressiveness)情感冷淡 Avolition/Amotivation (decreased motivation) Autistic behaviors (social withdrawal) Anhedonia (inability to experience pleasure )兴致缺乏 Ambivalence (coexistence of opposing attitudes or feelings) Anosognosia (impaired awareness of illness ) 3. Cognitive deficit Signs & Symptoms

9. Criteria A) Symptoms (positive and negative) B) Social and occupational decline C) Duration - longer than 6 months Exclusions Not another psychiatric condition, e.g. mood Not another medical condition, e.g. sarcoidosis Not drug abuse Not a pervasive developmental disorder全身性发育迟缓

10. Unaffected twin Schizophrenic twin MRIs of monozygotic twins show marked enlargement of the lateral ventricle in the twin with schizophreniz

11. A. 听觉-语言幻觉生产时的脑功能活动（PET） A B B. 视觉及听觉-语言幻觉生产时的脑功能活动（PET）

13. The Dopamine Hypothesis The dopamine hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy. Excessive dopaminergic activity plays a role in the disorder: • most antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic-frontal system; • drugs that increase dopaminergic activity, such as levodopa (a precursor), amphetamines (releasers of dopamine), or apomorphine (a direct dopamine receptor agonist), either aggravate schizophrenia or produce psychosis de novo in some patients; • dopamine receptor density has been found, postmortem, to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs; • PET has shown increased dopamine receptor density in both treated and untreated schizophrenics when compared with such scans of nonschizophrenic persons; and (5) successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid (HVA), a metabolite of dopamine, in the cerebrospinal fluid, plasma, and urine.

14. Brain dopaminergic pathways • Nigrostriatal pathway • (extrapyramidal motor control) • 2. Mesolimbic pathway • (psychomotor control) • 3. Mesocortical pathway • (psychomotor control) • 4. Tuberohypophyseal pathway (arcuate nucleus to pituitary gland) • (endocrine control, GH, ACTH↑, PRL↓) 1 3 Mesocortical pathway Tuberohypophyseal pathway 2 4

15. Dopaminergic pathways in the CNS and pharmacological effects of D2 antagonists A. mesolimbic and mesocortical pathways: related to psychological activities and the therapeutic effects of drugs. B. nigrostriatal pathway related to extrapyramidal adverse effects of drugs C. Tuberohypophyseal pathway related to hypothalamus endocrine adverse effects of drugs

16. ＤＡ／５ＨＴ平衡障碍学说 ＮＭＤＡＲ功能低下学说 其发病与遗传、社会环境、躯体生化代谢等因素有关

17. Classification of antipsychotics Typical: Phenothiazines (吩噻嗪类): chlorpromazine, etc Thioxanthenes (硫杂蒽类): chlorprothixene, etc Butyrophenones (丁酰苯类): haloperidol, etc Atypical: Clozapine, olanzapine, risperidone, aripiprazole, etc

18. Most-prescriped Medications Typical medications(D2 receptor antagonists) Low potency agents - Chlorpromazine (sedation) High potency agents - Haloperidol (motor problems – extrapyramidal effects) • Good ability to treat hallucinations and delusions in most people within approximately 2 months • Limited effect on negative symptoms

19. Most-prescriped Medications Typical medications (D2 receptor antagonists) Atypical agents Clozapine – D1, D2, 5-HT2 and D4 antagonist, great efficacy Olanzapine – 5-HT2, D1, D2, M, H, α antagonist, good Risperidone – 5-HT2 and D2 antagonist, good Aripiprazole – partial agonist of D2 and 5-HT1 , good

20. Historical Perspective • Chlorpromazine (氯丙嗪) made in 1950 in France, used to treat pre-operative anxiety • 1952 Delay and Deniker published the first report of Chlorpromazine's efficacy in psychosis • 1963 Carlsson and Lindqvist reported that Haloperidol and Chlorpromazine result in accumulation of DA metabolites

21. Chlorpromazine 1. Pharmacological effects (1) Central effects a) Antipsychotic effects (neuroleptic effects精神安定剂) -- controls excitation and then hallucinations (slow, weeks to months) b) Antiemetic effect止吐作用 -- inhibits chemoreceptor trigger zone (CTZ) in the medulla

22. Chlorpromazine c) Poikilothermic effects (comparison with NSAIDs) -- hypothermic anesthesia -- artificial hibernation (with meperidine哌替啶, promethazine异丙嗪) d) Extrapyramidal effects (nigrostriatal pathway blockade) --primary adverse effects e) Potentiating the effects of central depressants -- sedative-hypnotics, analgesics, general anesthetics, ethanol

23. Chlorpromazine (2) Effects on autonomic nervous system a) Hypotensive effects  receptor blockade, postural hypotension b) Anticholinergic effects dry mouth, constipation便秘, blurred vision视力模糊, urinary retention, increased intraocular pressure, etc.

24. Chlorpromazine (3) Endocrine effects (Tuberohypophyseal pathway blockade) Prolactin  (breast swelling, pain and lactation) Estrogen, progestin, ACTH, growth hormone

25. Chlorpromazine 2. Clinical uses (1) Treatment and prevention of acute schizophrenia and mania (2) Treatment of emesis and hiccough呃逆 but ineffective on motion sickness (3) Hypothermic anesthesia and artificial hibernation combined with lowering room temperature

26. 3. Side effects Motor disturbance (extrapyramidal syndrome, EPS ) - proportional to D2 blockade of nigrostriatal pathway Acute: dystonia (twisting and repetitive movements or abnormal postures肌张力失常), akathisia (inability to sit still), misnomer, stiffness, tremor (parkinsonism), occur commonly in the first few weeks, often declining with time, and are reversible. treated by central muscarinic antagonists Chlorpromazine

27. 3. Side effects Motor disturbance (EPS) Chlorpromazine • TD (tardive dyskinesia,迟发性运动障碍): Duo to supersensitive to DA : licking, sucking, chewing (twitching of the muscles around the mouth), described before meds existed, exacerbated in some, may be irreversible. Develops after months or years in 20-40% of patients. • Treatment is generally unsuccessful.

28. 3. Side effects NMS (neuroleptic malignant syndrome,神经阻滞药恶性综合征, induced by excessive blocking of DAergic system): high fever, hypertension, tonus, autonomic system disorder, mental confusion, even death. Chlorpromazine Treatment: DA agonists (egbromocriptine), DA releasers (egamantadine), and muscular relaxants (egscoline)

29. 3. Side effects Sedation, central depression Cardiac - lengthen QT interval, hypotension(block a receptor, over dose) Seizures Allergic reactions: skin reactions, leukopenia白细胞减少症, obstructive jaundice黄疸 Endocrine - prolactin elevation Drooling流涎 Weight gain Chlorpromazine

30. Contraindications • epilepsy • coma • elderly with CVS disorders • severe hepatic and renal dysfunction

31. Quiz Time Which one of the following drugs can be used to treat hypotension induced by chlorpromazine overdose? A Noradrenaline B Epinephrine C Isoprenaline D Phentolamine E Atropine

32. Haloperidol 氟哌啶醇 • High efficacy for positive symptoms • Weaker sedative effect • Weaker  and M receptor antagonism • More severe EPS(extrapyramidal syndrome, EPS ) • Less cardiac toxicity • Also can be used for anxiety, hiccup, vomiting Other typical antipsychotics: （氟）奋乃静、三氟拉嗪、氯普噻吨、氟哌噻吨、氟哌利多

33. “Atypical” Antipsychotics Atypical antipsychoticdrugsare used if extrapyramidal symptoms are troublesome, if symptom control is inadequate, or for newly diagnosed patients.

34. Then came clozapine (氯氮平) • Worked better than the rest (on some patients) • Relatively weak binding at dopamine D2 receptor, especially selective for the mesolimbic rather than the nigrostriatal pathways • Better efficacy at lower D2 receptor occupancy • Relatively stronger binding at serotonin receptors • “Dirty” drug - acts at many different types of receptors (D4, D2, 5-HT2) Other atypical antipsychotics: olanzapine (奥氮平), loxapine (洛沙平), risperidone (利培酮), aripirazole (阿立哌唑), etc.

35. “Atypical” Antipsychotics Many definitions: • Work better on positive symptoms ? - No • Work for “negative symptoms” ? – Some • Better cognitive effect- No • Less hormonal side effects ? - Prolactin - Sometimes • More easily tolerated? - equivocal, likely dose dependent • Less motor side effects ? - Yes

36. Case study --continued W.G. was taken to see a psychiatrist. He was diagnosed schizophrenia and hospitalized. Haloperidol was started at a dose of 10 mg/d. On the second day, he was found by the resident to develop a “seizure”. His neck was strained backward with his face turned upward toward the ceiling. He was having difficulty speaking but was quite conscious of his surroundings. The attending physician recognized this as an acute dystonia and ordered an immediate injection of benztropine. Haloperidol was replaced with loxapine accompanied with benztropine. 3 weeks later, his delusions and hallucinations disappeared and he developed insight into his problems. One month later, he left the hospital and resumed his academic life.

37. Compliance with Medication Studies show that 50% of all people do not consistently take medications as prescribed - all illnesses. Some studies have found as few as 20% of people take antipsychotics as recommended. Severe consequences to stopping medication Most significant advances on the horizon are likely going to involve improved compliance interventions (eg. new preparation)

38. 注意事项： 〔1〕小剂量开始用药，不宜反复更换用药，疗程一般4周 〔2〕本病容易复发，发作一次。阴性症状严重一次，所以往往需要持续治疗2年 〔3〕一般不主张联合用药，会导致医生无法判断那种药物起主要作用

39. Antidepressant Agents Depression (抑郁症) is a kind of mood disorders (mania, depression, bipolar) with symptoms such as intense feelings of sadness, hopelessness, despair, and inability to experience pleasure in usual activity.

40. Leading Sources of Disease Burden* • Ischemic Heart Disease • Unipolar Major Depression • Cardiovascular Disease • Alcohol Use • Traffic Accidents • Lung and other cancers • Dementia and Neurodegenerative Disorders *based on DALY’s (Disability Adjusted Life Years, WHO) which measure lost years of healthy life due to premature death or disability

42. Depressed Mood Loss of interest or pleasure in almost all activities Significant weight loss or gain or change in appetite nearly every day Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or inappropriate guilt Diminished ability to think or concentrate; indecisiveness Recurrent thoughts of or attempts at suicide; wishing one were dead Criteria for Diagnosis of Major Depression At least 2 weeks of ≥5 of the above features, which are present most of the day or nearly every day; must include depressed mood or loss of interest or pleasure.

43. Monoamine Hypothesis of Depression • Functional deficiency of norepinephrine (NE) or serotonin (5-Hydroxytryptamine, 5-HT) in the brain is key to the pathology and behavioral manifestations associated with depression.

44. 兰斑核

45. 中缝核

47. Classifications of Antidepressants • Tricyclic Antidepressants (TCAs，三环类抗抑郁药) and heterocyclics • Selective Serotonin Reuptake Inhibitors (SSRIs) • Selective Norepinephrine Reuptake Inhibitors (NRIs) • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) • Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) • Monoamine Oxidase Inhibitors (MAOIs) • Norepinephrin-Serotonin Releasers

50. TCAs are highly related in their chemical structures 氯丙咪嗪 阿米替林 丙咪嗪 去甲替林 地昔帕明 Doxepin 多塞平 NRIs