Transcript 张世红_精神药物与成瘾控制

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
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Antipsychotic Agents
----Schizophrenia is a particular kind of
psychosis characterized by a clear sensorium
but a marked thinking disturbance
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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.
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Schizophrenia
• Neurological disorder - impaired ability to perceive,
understand & interpret the environment
• Impaired social and occupational function
• Behavioral syndrome – predictable or not
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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
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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)
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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 )
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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)
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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
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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
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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
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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
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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
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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
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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.
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Chlorpromazine
(3) Endocrine effects (Tuberohypophyseal
pathway blockade)
Prolactin  (breast swelling, pain and lactation)
Estrogen, progestin, ACTH, growth hormone 
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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
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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.
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Chlorpromazine
3. Side effects
• Motor disturbance (extrapyramidal
syndrome, EPS )
- Acute dystonia
mAChR antagonists may
counteract acute dystonia
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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.
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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)
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Chlorpromazine
3. Side effects
•
•
•
•
•
•
Sedation
Cardiac - lengthen QT interval, hypotension
Seizures
Endocrine - prolactin elevation
Drooling
Weight gain
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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
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Haloperidol 氟哌啶醇
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•
•
•
•
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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
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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.
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“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
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“Atypical” Antipsychotics
Atypical antipsychotic drugs are used if
extrapyramidal symptoms are troublesome, if
symptom control is inadequate, or for newly
diagnosed patients.
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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
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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)
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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.
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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.
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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.
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中缝核
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兰斑核
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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
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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
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TCAs
Mechanisms: Non-selective monoamines (mainly
NE and 5-HT) reuptake inhibitors
Clinical uses: depression, anxiety, obsessive
compulsive disorder, panic disorder, neuropathic
pain, enuresis
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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Alternative Treatments for
Depression
• Electroconvulsive Therapy
• Transcranial Magnetic Stimulation
• Exercise
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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
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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)
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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
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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
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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
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Antimanic Drugs
- Lithium carbonate
- Antiphsychotics
- Antiepileptics
- Calcium channel blockers
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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.
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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
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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
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Management of drug dependence
药物依赖（成瘾）性的控制
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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.
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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
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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。
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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。
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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.
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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）>
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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）>
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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
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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
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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
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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
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