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Drugs Used to Treat Psychiatric Disorders Shi-Hong Zhang (张世红), Ph.D, Associate Prof. [email protected] 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 2 Antipsychotic Agents ----Schizophrenia is a particular kind of psychosis characterized by a clear sensorium but a marked thinking disturbance 3 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. 4 Schizophrenia • 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 Signs & Symptoms 1. Positive symptoms • 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) 7 Signs & Symptoms 2. Negative symptoms • Affective flattening (absence of emotional expressiveness) • Avolition/Amotivation (decreased motivation) • Autistic behaviors (social withdrawal) • Anhedonia (inability to experience pleasure ) • Ambivalence (coexistence of opposing attitudes or feelings) • Anosognosia (impaired awareness of illness ) 8 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 • D2 hypothesis (excessive dopaminergic activity plays a role in the disorder) – supported by increased dopamine receptor density and “potency” of DA antagonism at D2 related to efficacy. • Refs: http://www.bedrugfree.net/Schizophrenia.pdf Film: One Flew Over the Cuckoo’s Nest (1975) 9 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 10 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 11 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 12 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 13 Chlorpromazine 1. Pharmacological effects (1) Central effects a) Antipsychotic effects (neuroleptic effects) -- controls excitation and then hallucinations (slow, weeks to months) b) Antiemetic effect -- inhibits chemoreceptor trigger zone (CTZ) in the medulla 14 Chlorpromazine c) Poikilothermic effects (comparison with NSAIDs) -- hypothermic anesthesia -- artificial hibernation (with meperidine, promethazine) d) Extrapyramidal effects (nigrostriatal pathway blockade) -- primary adverse effects e) Potentiating the effects of central depressants -- sedative-hypnotics, analgesics, general anesthetics, ethanol 15 Chlorpromazine (2) Effects on autonomic nervous system a) Hypotensive effects receptor blockade, postural hypotension b) Anticholinergic effects dry mouth, constipation, blurred vision, urinary retention, increased intraocular pressure, etc. 16 Chlorpromazine (3) Endocrine effects (Tuberohypophyseal pathway blockade) Prolactin (breast swelling, pain and lactation) Estrogen, progestin, ACTH, growth hormone 17 Chlorpromazine 2. Clinical uses (1) Treatment and prevention of acute schizophrenia and mania (2) Treatment of emesis and hiccough but ineffective on motion sickness (3) Hypothermic anesthesia and artificial hibernation combined with lowering room temperature 18 Chlorpromazine 3. Side effects • Motor disturbance (extrapyramidal syndrome, EPS ) - proportional to D2 blockade of nigrostriatal pathway - Acute: dystonia (twisting and repetitive movements or abnormal postures), akathisia (inability to sit still), misnomer, stiffness, tremor (parkinsonism), occur commonly in the first few weeks, often declining with time, and are reversible. 19 Chlorpromazine 3. Side effects • Motor disturbance (extrapyramidal syndrome, EPS ) - Acute dystonia mAChR antagonists may counteract acute dystonia 20 Chlorpromazine 3. Side effects • Motor disturbance (EPS) - TD (tardive dyskinesia): 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. 21 Chlorpromazine 3. Side effects • NMS (neuroleptic malignant syndrome, induced by excessive blocking of DAergic system): high fever, hypertension, tonus, autonomic system disorder, mental confusion, even death. Treatment: DA agonists (eg bromocriptine), DA releasers (eg amantadine), and muscular relaxants (eg scoline) 22 Chlorpromazine 3. Side effects • • • • • • Sedation Cardiac - lengthen QT interval, hypotension Seizures Endocrine - prolactin elevation Drooling Weight gain 23 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 24 Haloperidol 氟哌啶醇 • • • • • • High efficacy for positive symptoms Weaker sedative effect Weaker and M receptor antagonism More severe 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 25 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. 26 “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 27 “Atypical” Antipsychotics Atypical antipsychotic drugs are used if extrapyramidal symptoms are troublesome, if symptom control is inadequate, or for newly diagnosed patients. 28 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 29 resumed his academic life. 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) 30 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. 32 Criteria for Diagnosis of Major Depression • Depressed Mood • Fatigue or loss of energy • Loss of interest or pleasure in almost all activities • Feelings of worthlessness or inappropriate guilt • Significant weight loss or gain or change in appetite nearly every day • Diminished ability to think or concentrate; indecisiveness • Insomnia or hypersomnia • Psychomotor agitation or retardation • Recurrent thoughts of or attempts at suicide; wishing one were dead 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. 33 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. 34 中缝核 35 兰斑核 36 37 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 38 39 40 TCAs are highly related in their chemical structures 丙咪嗪 Doxepin 多塞平 氯丙咪嗪 阿米替林 去甲替林 地昔帕明 NRIs 41 TCAs Mechanisms: Non-selective monoamines (mainly NE and 5-HT) reuptake inhibitors Clinical uses: depression, anxiety, obsessive compulsive disorder, panic disorder, neuropathic pain, enuresis 42 Side effects Toxicity - Narrow dose response range. Normal plasma levels 0.1-0.2 mg/ml Toxic effects are seen at 1.0 mg/ml Anticholinergic - dry mouth, constipation, dizziness, blurred vision, tachycardia, urinary retention Hypotension and Sedation - due to adrenergic blocking properties and/or anti-histaminergic 43 Selective norepinephrine reuptake inhibitors (NRIs) 尼索西汀 地昔帕明 托莫西汀 去甲替林 瑞波西汀 Amoxapine 阿莫沙平 44 45 Selective serotonin reuptake inhibitors (SSRIs): used for both anxiety and depression 氟西汀,百忧解 氟伏沙明 舍曲林 西酞普兰 帕罗西汀 茚达品 46 Side effects • GI upset, weight gain and low libido • Serotonin Syndrome: - Occurs when switching among SSRIs or to other drug classes - Potential for over-activation of central serotonin receptors - Features: abdominal pain, diarrhea, sweating, fever, tachycardia, increased blood pressure, tremor and altered mental state, or even coma and death Eric Harris Fluvoxamine taker (Luvox) Dylan Klebold 47 Columbine High School massacre Norepinephrine-dopamine reuptake inhibitors (NDRIs) Bupropion 安非他酮 • Glaxo Wellcome product • Inhibits NE, DA and serotonin reuptake • No weight gain or sexual dysfunction 48 Serotonin-norepinephrine reuptake inhibitors (SNRIs) 度洛西汀 文拉法辛 Used for: depression generalized anxiety disorder obsessive compulsive disorder panic attacks neuropathic pain Adverse effects: GI upset, headache, insomnia 49 Monoamine Oxidase Inhibitors (MAOIs) MAO: ---Regulates free intraneuronal concentration of NE or 5-HT ---Regulates inactivation of endogenous and ingested amines Side effects: few anticholinergic, adrenergic side effects but toxicity associated with dietary interactions (tyramine酪胺) Non-selective MAO-A selective 司来吉兰 MAO-B selective Non-selective 吗氯贝胺 50 MAOIs and Dietary Interactions • Tyramine is normally metabolized by MAO • Tyramine is sympathomimetic (it acutely displaces NE from terminals to activate receptors) • Ingesting tyramine during MAO inhibition results in hypertension, headache, palpitations, nausea, vomiting • Tyramine is present in a number of foodstuffs, such as aged cheese, red wine, soybean products, etc. 51 52 Norepinephrin-serotonin releaser - Mirtazapine (米氮平) - Blocks presynaptic 2 receptor - Promotes the release of NA and 5-HT - Weight gain and postural hypotension are main adverse effects 53 Clinical Pharmacology of Antidepressants • Depression: antidepressants, lithium • Panic disorder: benzodiazepine, SSRIs, MAOIs • Obsessive-compulsive disorders: selective and mixed serotonin reuptake inhibitors • Enuresis: tricyclics • Neuropathic pain: tricyclics, norepinephrine reuptake inhibitors 54 Individualized Therapy • Drug choice • Dosages: from small doses • Maintenance treatment: 6-8 months after remission, gradually withdraw • Monitoring plasma concentrations • Unresponsive patients: diagnosis, drug, dose, duration of treatment (6-8wks), and different treatments 55 Alternative Treatments for Depression • Electroconvulsive Therapy • Transcranial Magnetic Stimulation • Exercise 56 Electroconvulsive Therapy • Brief electrical pulse to the scalp under anesthesia • Neurons are excited causing them to fire in unison and produce a seizure • Mechanism of effectiveness is unknown 57 Electroconvulsive Therapy • 1930s: used for numerous psychiatric illnesses • 1970s: improved treatment delivery, increased safety and comfort resulted in increased use • Most effective in severe depression and medication response failure • Treatments are administered up to 3 times a week for a course of 6-12 treatments total • Effects can be seen more rapidly (1-2 weeks) than typical pharmacotherapy (3-6 weeks) 58 Transcranial Magnetic Stimulation • Safe and noninvasive means of getting electrical energy into the brain • Procedure involves discharge of a large current (5000 amps) through a copper-wire coil • Magnetic field produces currents in the induced electrical field lying parallel to the plane of the coil • Currents can excite axons lying in the plane of the induced field in a manner similar to that achieved with direct cortical stimulation with electrodes 59 Transcranial Magnetic Stimulation • Repetitive TMS (rTMS) • Similar to ECT but less intense and given over specific areas of the brain for a longer time than ECT • No anesthesia or seizure production 60 Exercise Exercise as an augmenting Treatment for major Depressive Disorder: A Pilot Study Friedman. R., et al, Society for Neuroscience 2003 Abstract 851.9 *treadmill, walking or cycling for 12 weeks, 30 min for most days of the week 61 Antimanic Drugs - Lithium carbonate - Antiphsychotics - Antiepileptics - Calcium channel blockers 62 Antimanic Drugs Lithium carbonate • Lithium is an anti-mania drug with narrow TI; • Start with small dosage. Dosage regimens should be individually titrated to desired concentrations and clinical response of the patients; • The toxicity should be monitored regularly; • The patients and/or their families should be educated. 63 Therapeutic range of lithium Disease or condition Therapeutic range Acute mania 0.5-1.2 mmol/L 1.2-1.5 mmol/L may be required in selected patients Prophylaxis of mania and/or depression 0.6-0.8 mmol/L 64 Concentration-related toxicity of lithium Potential side effects under therapeutic concentrations: Agitation, cogwheel rigidity, confusion, delirium, dysarthria, increased deep tendon reflexes, memory impairment, seizures. Mild toxicity (>1.5 mmol/L): Fatigue, fine tremors of the limbs, gastrointestinal disturbances, muscle weakness Moderate toxicity (1.5-2.5 mmol/L): Ataxia, coarse tremors, dysarthria, headaches, hyperthermia, impaired sensorium, increased deep tendon reflexes, lethargy, nystagmus, sedation Severe toxicity (>2.5 mmol/L): Basal ganglia dysfunction, coarse tremors, delirium, respiratory complication, seizures, death 65 Management of drug dependence 药物依赖(成瘾)性的控制 66 Definition of drug dependence Drug dependence is a condition resulting from the prolonged and usually intense consumption of a drug or drugs which has resulted in psychological and/or physiological dependence on drug consumption. 67 Manifestation of drug dependence 1、精神依赖性(psychological dependence, psychic dependence) 精神依赖性是指使人产生一种对药物欣快感的渴 求,这种精神上不能自制的强烈欲望驱使滥用者周 期性或连续地用药。是判断药物是否具有成瘾性的 必要条件。 又被称为情感动机依赖性 68 Manifestation of drug dependence 2、身体依赖性(physical dependence) 指大多数具有依赖性特征的药物经过反复使用 所造成的一种适应状态,用药者一旦停药,将发 生一系列生理功能紊乱,称戒断综合征 (withdrawal syndrome)。不是判断药物具有 成瘾性的条件,但常伴随药物成瘾。 69 Manifestation of drug dependence 3、药物成瘾(drug addiction) 药物成瘾是指强迫性、失去控制、不计后果的用 药行为,是药物的精神依赖性和生理依赖性共同 造成的结果。 4、药物滥用(drug abuse) 是指与医疗目的无关的反复使用能成瘾的药物, 可为药物成瘾的原因或结果。 70 From: Substance Abuse and Mental Health Services Administration, 2005 National Survey on Drug Use and Health. Number of individuals with drug dependence in five million persons aged 12 or older. 71 Drugs with dependence potential • 麻醉药品 (narcotic drugs):连续使用后易产生 身体和精神依赖的药品。 阿片类(Opioids):吗啡,海洛因,etc 可卡因 (Cocaine) 大麻类(Cannabinoids):大麻(脂) 合成麻醉药类(Synthetical drugs):哌替啶,美沙酮,等 其它易成瘾癖的药品等,共123种 <麻醉药品和精神药品品种目录(2007年版)> 72 Drugs with dependence potential • 精神药品 (psychotropic drugs):作用于中枢神经系统, 能使之兴奋或抑制,反复应用能产生精神依赖性的药品。 第一类:氯胺酮,司可巴比妥(速可眠)、丁丙诺非、哌醋甲酯 (利他林),苯丙胺,三唑仑、齐培丙醇等53种 第二类: - 咖啡因,安钠咖 - 巴比妥类(戊巴比妥,巴比妥、苯巴比妥) - 氨酚待因,氯氮卓(利眠宁),卡马西平,去甲伪麻黄碱 - 西泮类(氯硝西泮、氟西泮、地西泮) - 唑仑类(阿普唑仑、艾司唑仑) - 氨甲丙酯等88种 <麻醉药品和精神药品品种目录(2007年版)> 73 74 75 Mechanisms of drug dependence 阿片类 μ受体激动 可卡因 抑制单胺类神经递质转运体 苯丙胺类 促进单胺类神经递质释放(通过抑制囊泡单胺类神 经递质转运体) 增强GABAA受体功能,抑制NMDA受体功能(尚 不清楚是直接作用于靶分子还是通过间接作用) 乙醇 尼古丁 N胆碱受体激动 大麻类 CB1受体激动 致幻剂 5-HT2A受体部分激动药 苯环己哌啶、氯胺酮 NMDA受体非竞争性阻断药 挥发性有机溶剂 不明 76 Prevention of drug dependence • 药物依赖是可以预防的 • 患者教育 • 严格管理,科学处方,合理用药 eg,麻醉性镇痛药按时给药而非按需给药 77 Management of drug dependence Principles of drug dependence treatment: (1) Medications are an important element of treatment for many patients, especially when combined with counseling and other behavioral therapies (2) No single treatment is appropriate for everyone Goals of drug dependence treatment: (1) Abstinence (withdrawal therapy, detoxification) (2) Relapse prevention (3) Rehabilitation 78 Management of drug dependence 阿片类戒毒治疗: (1) 阿片类替代法 (substitute therapy):美沙酮 (methadone)、哌替啶、丁丙诺啡、可待因; (2)可乐定(clonidine)疗法:可抑制NE释放,抑制戒断反应症状; (3)东莨菪碱综合戒毒法:以东莨菪碱为主、氯丙嗪为辅治疗; (4)复吸预防:脱瘾后服用纳曲酮(naltrexone),美沙酮长期维持 治疗; (5)精神心理方面的对症治疗 http://www.moh.gov.cn/mohbgt/index.shtml http://www.ncbi.nlm.nih.gov/books/NBK64164/pdf/TOC.pdf 79