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Drugs Used to Treat Psychiatric Disorders

Drugs Used to Treat Psychiatric Disorders. Shi-Hong Zhang ( 张世红 ), Ph.D, Associate Prof. shzhang713@zju.edu.cn. Psychiatric Disorders. Lifetime prevalence: about 1/3- 1/2 of population - Mood Disorder: 8-10% - Anxiety Disorder: 15% - Substance abuse: 16% - Schizophrenia: 1%

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Drugs Used to Treat Psychiatric Disorders

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  1. Drugs Used to Treat Psychiatric Disorders Shi-Hong Zhang (张世红), Ph.D, Associate Prof. shzhang713@zju.edu.cn

  2. 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

  3. Antipsychotic Agents ----Schizophrenia is a particular kind of psychosis characterized by a clear sensorium but a marked thinking disturbance

  4. 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.

  5. Schizophrenia Neurological disorder - impaired ability to perceive, understand & interpret the environment Impaired social and occupational function Behavioral syndrome – predictable or not

  6. 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

  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) 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 ) Signs & Symptoms

  9. 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)

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

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

  18. 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

  19. 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. Chlorpromazine

  20. 3. Side effects Motor disturbance (extrapyramidal syndrome, EPS ) - Acutedystonia Chlorpromazine mAChR antagonists may counteract acute dystonia

  21. 3. Side effects Motor disturbance (EPS) Chlorpromazine • 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.

  22. 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. Chlorpromazine Treatment: DA agonists (egbromocriptine), DA releasers (egamantadine), and muscular relaxants (egscoline)

  23. 3. Side effects Sedation Cardiac - lengthen QT interval, hypotension Seizures Endocrine - prolactin elevation Drooling Weight gain Chlorpromazine

  24. 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

  25. 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

  26. 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.

  27. “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

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

  29. 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.

  30. 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)

  31. 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. 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.

  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. 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

  37. 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

  38. TCAs Mechanisms:Non-selective monoamines (mainly NE and 5-HT) reuptake inhibitors Clinical uses: depression, anxiety, obsessive compulsive disorder, panic disorder, neuropathic pain, enuresis

  39. 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

  40. Selective norepinephrine reuptake inhibitors (NRIs) 瑞波西汀 托莫西汀 尼索西汀 Amoxapine 阿莫沙平 去甲替林 地昔帕明

  41. Selective serotonin reuptake inhibitors (SSRIs): used for both anxiety and depression 舍曲林 帕罗西汀 氟西汀，百忧解 茚达品 氟伏沙明 西酞普兰

  42. 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 Dylan Klebold Fluvoxamine taker (Luvox) Columbine High School massacre

  43. Norepinephrine-dopamine reuptake inhibitors (NDRIs) Bupropion • Glaxo Wellcome product • Inhibits NE, DA and serotonin reuptake • No weight gain or sexual dysfunction 安非他酮

  44. Serotonin-norepinephrine reuptake inhibitors (SNRIs) 文拉法辛 度洛西汀 Used for: depression generalized anxiety disorder obsessive compulsive disorder panic attacks neuropathic pain Adverse effects: GI upset, headache, insomnia

  45. Monoamine Oxidase Inhibitors (MAOIs) MAO: ---Regulates free intraneuronal concentration of NE or 5-HT ---Regulates inactivation of endogenous and ingested amines Non-selective Side effects: few anticholinergic, adrenergic side effects but toxicity associated with dietary interactions (tyramine酪胺) MAO-A selective 司来吉兰 MAO-B selective Non-selective 吗氯贝胺

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