drugs used in the treatment of psychological disorders §antipsychotic drugs §antidepressant and...

Drugs used in the Treatment Drugs used in the Treatment of Psychological Disordersof Psychological Disorders

Antipsychotic drugsAntipsychotic drugs Antidepressant and antimanic drugsAntidepressant and antimanic drugs AnxiolyticsAnxiolytics

2012.5.14

5.14

周一 8:00-8:45 成瘾的神经生物学机制 1 包爱民9:50-10:35 精神药物治疗 1 陈忠10:40-11:25 药物成瘾性的控制 1 陈忠13:15-16:40 临床基本穿刺（胸穿、腰穿）练习 4 王一红

5.8 周二8:00-8:45 情绪的脑机制 1 周煜东8:50-9:35 精神分裂症的病因学 1 周煜东9:50-10:35 精神分裂症的神经生物学 1 周煜东

5.9 周三

8:00-8:45 精神分裂症的主要临床表现 1 李惠春8:50-9:35 精神分裂症的诊断标准 1 李惠春9:50-10:35 自杀、法律能力的评定 1 陈炜13:15-16:40 CPR 培训 4 张悦怡、王一红

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；以丙米嗪 ( 米帕明 ) 为代表，抗抑郁药的药理作用和作用机制 ( 阻断 NA 和 5-HT 再摄取 ) 、临床应用。

了解：其他主要药物的特点。

Psychiatric Disorders (in general)

Lifetime prevalence: about 1/3- 1/2 of population

Substance abuse: 16%Schizophrenia: 1%Affective Disorder: 8-10%Anxiety Disorder: 15%

Epidemiology

• Incidence consistent worldwide 1% general population 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 Urban setting > rural setting

• Age of onset Men 17 – 27, Women 17 - 37 Childhood onset extremely rare: 1 in 10,000-

100,000

• Duration – life

• Outcome 10 % good - optimistic 80% remission without full recovery 10 % no remission

Signs & Symptoms

Positive symptoms• Delusions ( 错觉 )- fixed false belief outside

cultural norm (bizarre vs. non bizarre)• Hallucinations ( 幻觉 )- perceptual (hearing), have

no outside source • “Like my voice”

• Not an illusion ( 幻想， a mistaken perception for which there is an actual external stimulus)

• Disorganization - pattern of speech or behavior, making up words without a meaning (neologisms)

Negative symptoms• Affective flattening 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 )

Cognitive deficit

Signs & Symptoms

Criteria

A) Symptoms (positive and negative)B) Social and occupational declineC) Duration - longer than 6 monthsExclusions

Not another psychiatric condition, e.g. moodNot another medical condition, e.g. sarcoidosisNot drug abuseNot a pervasive developmental disorder 全身性发

育迟缓

DA 学说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

Classification of antipsychotics

Typical:

Phenothiaazines ( 吩噻嗪类 ): chlorproomazineThioxanthenes ( 硫杂蒽类 ): chlorprothixene 氯普噻吨（泰尔登）

Buutyrophenones ( 丁酰苯类 ): halopeeridol 氟哌啶醇

Atypical:Clozapine, olanzapine 奥氮平 , risperidone 利培酮

Available MedicationsTypical medications (D2 receptor antagonists)

Low potency agents - Chlorpromazine (sedation) High potency agents - Haloperidol (motor problems –

extrapyramidal effects)

Atypical agents Clozapine – 5-HT2 and D4 receptor antagonist, great efficacy Olanzapine （奥氮平）– 5-HT2, D1, D2, M, H, αreceptor

antagonist, good Risperidone （利培酮）– 5-HT2 and D2 receptor antagonist,

good Aripiprazole （阿立哌唑） – partial agonist of D2 and 5-HT1

receptor

A.A. Antipsychotic drugs Antipsychotic drugs1. The dopamine hypothesis of schizophrenia

2. The serotonin hypothesis of schizophrenia

3. The glutamate hypothesis of schizophrenia

黑质黑质 -- 纹状体通纹状体通路路

中脑中脑 -- 皮层通皮层通路路

结节结节 -- 漏斗通漏斗通路路

PhenothiazinesPhenothiazines （吩噻嗪类）（吩噻嗪类）

Chlorpromazine Chlorpromazine 氯丙嗪氯丙嗪

N

S

(CH2)3

Cl

N(CH3)2

A.A. Antipsychotic drugs Antipsychotic drugs

• 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 Lindquist report that Haloperidol and Chlorpromazine result in

accumulation of DA metabolites

• D2 hypothesis (excessive dopaminergic activity plays a role in the disorder) - 1976 Seeman et. al.

and Creese et. al. report that “potency” of DA antagonism at D2 related to efficacy

Good & Gilman


(1) Central effects: (1) Central effects: Blocking central DBlocking central D22 dopamine dopamine

receptorsreceptors

a) Antipsychotic effects (neuroleptic effects)a) Antipsychotic effects (neuroleptic effects)

镇静和抗精神病作用镇静和抗精神病作用 for treatment of for treatment of schizophreniaschizophrenia controlling excitation and then hallucinations controlling excitation and then hallucinations

((weeks to monthsweeks to months))

b) Antiemetic effects b) Antiemetic effects 镇吐作用镇吐作用 inhibiting inhibiting chemoreceptor trigger zonechemoreceptor trigger zone (CTZ) (CTZ)

dopaminergic functiondopaminergic function


c) Poikilothermic effects c) Poikilothermic effects 体温调节作用体温调节作用 hypothermic anesthesiahypothermic anesthesia artificial hibernationartificial hibernation

d) Extrapyramidal effects d) Extrapyramidal effects 椎体外系作用椎体外系作用 primary adverse effectsprimary adverse effects

e) e) Potentiating the effects of central depressantsPotentiating the effects of central depressants sedative-hypnotics, analgesics, general anesthetics, sedative-hypnotics, analgesics, general anesthetics,

ethanolethanol


(2) Autonomic nervous system effects(2) Autonomic nervous system effects

a) Hypotensive effectsa) Hypotensive effects receptor blockade, receptor blockade, postural hypotensionpostural hypotension

b) Anticholinergic effectsb) Anticholinergic effectsddry mouth, constipation, blurred vision, ry mouth, constipation, blurred vision,

urinary retention, ect.urinary retention, ect.

(3) Endocrine effects(3) Endocrine effects prolactin prolactin ACTH, growth hormone ACTH, growth hormone


2. 2. Clinical usesClinical uses

(1) Treatment of schizophrenia(1) Treatment of schizophrenia

(2) Treatments of emesis ((2) Treatments of emesis ( 呕吐呕吐 )and hiccough()and hiccough( 呃逆呃逆 )) used forused for emesisemesis andand hiccoughhiccough but ineffective on motion sicknessbut ineffective on motion sickness

(3) Hypothermic anesthesia and artificial hibernation(3) Hypothermic anesthesia and artificial hibernation combined with lowering room temperaturecombined with lowering room temperature


3. 3. Adverse effectsAdverse effects

(1) Side effects(1) Side effects central depressioncentral depression peripheral effects:peripheral effects: postural hypotensionpostural hypotension, ,

dry mouth, and other effects resulting from dry mouth, and other effects resulting from muscarinic and muscarinic and receptor blockade receptor blockade


(2) Extrapyramidal effects(2) Extrapyramidal effects

Due to DA receptor block:Due to DA receptor block: a) Parkinsonisma) Parkinsonism b) Akathisia (b) Akathisia ( 静坐不能静坐不能 )) c) Acute dystonia (c) Acute dystonia ( 急性肌张力障碍急性肌张力障碍 ))

attenuated by central muscarinic antagonistsattenuated by central muscarinic antagonists

Due to supersensitive to DA:Due to supersensitive to DA: Tardive dyskinesiaTardive dyskinesia (( 迟发性运动障碍迟发性运动障碍 ))


(3) Other central reactions(3) Other central reactions 药源性疾病药源性疾病 neuroleptic maglinant syndrome neuroleptic maglinant syndrome (( 神经阻滞药恶性综合神经阻滞药恶性综合

征）征） (NMS, induced by excessive blocking of DAergic system): high fever, hypertension, tonus, autonomic system disorder, even death

psychotic reactionspsychotic reactions epilepsy and convulsion: lowering seizure thresholdepilepsy and convulsion: lowering seizure threshold

(4) Allergic and hemological reactions(4) Allergic and hemological reactions skin reactions, leukopenia, skin reactions, leukopenia, obstructive jaundice, obstructive jaundice,

liver damageliver damage


Treatment: DA agonists (eg bromocriptine), DA releasers (eg amantadine),

and muscular relaxants (eg scoline)

(5) CVS reactions (5) CVS reactions arrhythmiaarrhythmia hypotension: treated byhypotension: treated by receptor agonists receptor agonists sudden death (elderly with CVS diseases)sudden death (elderly with CVS diseases)

(6) Endocrine reactions(6) Endocrine reactions hyperplasia of mammary glands (hyperplasia of mammary glands ( 乳腺增生乳腺增生 ), ),

galactorrhea (galactorrhea ( 溢乳溢乳 ), amenorrhea (), amenorrhea ( 闭经闭经 ),), child growth retardchild growth retard


(6) Acute intoxication(6) Acute intoxication severe CNS depression, coma, severe hypotensionsevere CNS depression, coma, severe hypotension

(7) Contraindications(7) Contraindications epilepsyepilepsy comacoma elderly with CVS disorderselderly with CVS disorders severe hepatic and renal dysfunctionsevere hepatic and renal dysfunction


Other phenothiazinesOther phenothiazines

perphenazine perphenazine 奋乃静奋乃静

fluphenazine fluphenazine 氟奋乃静氟奋乃静

trifluoperazine trifluoperazine 三氟拉嗪三氟拉嗪

thioridazine thioridazine 硫利达嗪硫利达嗪

more potent therapeutic effects and more potent therapeutic effects and extrapyramidal effectsextrapyramidal effects


Thioxanthenes Thioxanthenes (( 硫杂蒽类硫杂蒽类 )) ：结构与三环类抗：结构与三环类抗抑郁药相似抑郁药相似

ChlorprothixeneChlorprothixene 氯普噻吨（泰尔登）氯普噻吨（泰尔登）

Used for the patients with symptoms of Used for the patients with symptoms of depressiondepression and and anxietyanxiety


ButyrophenonesButyrophenones （丁酰苯类）（丁酰苯类）

Haloperidol Haloperidol 氟哌啶醇氟哌啶醇

Droperidol Droperidol 氟哌利多（氟哌啶）氟哌利多（氟哌啶）

Combined with fentanylCombined with fentanyl （芬太尼）（芬太尼） ::

neuroleptanalgesianeuroleptanalgesia （神经安定（神经安定 [[ 镇痛镇痛 ] ] 麻醉术）麻醉术）


OthersOthers Penfluridol Penfluridol 五氟利多五氟利多 Longer duration of action, taking once weeklyLonger duration of action, taking once weekly

Sulpride Sulpride 舒必利舒必利

selectively acts on mesolimbic Dselectively acts on mesolimbic D22 receptors receptors

few extrapyramidal reactions few extrapyramidal reactions

Clozapine Clozapine 氯氮平氯氮平

Blocking DBlocking D44 and 5-HT receptors and 5-HT receptors

Risperidone Risperidone 利培酮利培酮

Blocking Blocking DD22 and 5-and 5-HTHT22 receptors receptors


Disorders of MoodDisorders of Mood

Disorders of mood Disorders of mood ((affective disordersaffective disorders 情感障碍情感障碍 )) are are extremely common in medical practice. The extremely common in medical practice. The severity of these conditions covers an severity of these conditions covers an extraordinarily broad range, from normal extraordinarily broad range, from normal grief reactions and dysthymia to severe, grief reactions and dysthymia to severe, incapacitating illness that may result in death.incapacitating illness that may result in death.

EmotionEmotion （（情绪情绪）） refers to transient responses to refers to transient responses to environmental, internal, and cognitive stimuli, environmental, internal, and cognitive stimuli, while while moodmood （（心境心境）） refers to the predominant refers to the predominant emotional state over time.emotional state over time.

The symptoms of The symptoms of depressiondepression are intense feelings of are intense feelings of sadness, hopelessness, despair, and inability to sadness, hopelessness, despair, and inability to experience pleasure in usual activity.experience pleasure in usual activity.

ManiaMania is characterized by the opposite behavior, is characterized by the opposite behavior, that is, enthusiasm, rapid thought and speech that is, enthusiasm, rapid thought and speech patterns, and extreme self-confidence and impaired patterns, and extreme self-confidence and impaired judgment.judgment.

AnxietyAnxiety, a state characterized by arousal, vigilance, , a state characterized by arousal, vigilance, physiologic preparedness, and negative subjective physiologic preparedness, and negative subjective states, may share certain critical circuits with states, may share certain critical circuits with fearfear..

Disorders of MoodDisorders of Mood

Monoamine hypothesisMonoamine hypothesis （单胺假说）（单胺假说）

5-HT 5-HT — genetic basis of depression & mania — genetic basis of depression & mania

NE NE — — depressiondepression

NE NE — — maniamania

Modulation of monoamines in the synaptic space Modulation of monoamines in the synaptic space and/or the related post-synaptic receptors is of and/or the related post-synaptic receptors is of therapeutic importancetherapeutic importance

B.B. Antidepressant Drugs Antidepressant Drugs

Modulation of monoamines Modulation of monoamines ((NENE and and 5-HT5-HT) in the ) in the synaptic space and/or the synaptic space and/or the related post-synaptic related post-synaptic receptors is of therapeutic receptors is of therapeutic importanceimportance

Long-term adaptations to antidepressant treatmentLong-term adaptations to antidepressant treatmentMolecular pharmacology

Model of the neurotrophic Model of the neurotrophic hypothesis ofhypothesis ofantidepressant treatments and antidepressant treatments and stress-related disordersstress-related disorders


Enhancement of monoamine (5-HT, NE) Enhancement of monoamine (5-HT, NE) transmitter functiontransmitter function

Inhibition of monoamine reuptakeInhibition of monoamine reuptake

Inhibition of monoamine degradationInhibition of monoamine degradation

May decrease the number and sensitivity of NE and 5-HT receptors

Tricyclic/polycyclic antidepressants

Monoamine oxidase inhibitor


NE and 5-HT reuptake inhibitor (SNRIs)

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

NE reuptake inhibitor (NARIs)

Selective 5-HT reuptake inhibitors (SSRIs)

Imipramine Imipramine 丙咪嗪丙咪嗪（米帕明）（米帕明）

N

CH2CH2CH2NCH3

CH3

Tricyclic Tricyclic structurestructure


1. 1. Pharmacological effectsPharmacological effects

(1) Central effects (1) Central effects Inhibiting reuptake of monoamine transmittersInhibiting reuptake of monoamine transmitters

include NA and 5-HTinclude NA and 5-HT Improving patient’s Improving patient’s mood after 2 weeksmood after 2 weeks Sedative effects in normal subjects (Sedative effects in normal subjects (1 and H1 1 and H1

receptor)receptor) Extrapyramidal effects (D2 receptor)Extrapyramidal effects (D2 receptor)

(2) Autonomic effects(2) Autonomic effects Muscarinic blocking effectsMuscarinic blocking effects

(3) Cardiovascular effects ((3) Cardiovascular effects ( receptor receptor)) Hypotension, tachycardia, arrhythmiaHypotension, tachycardia, arrhythmia


2. 2. Clinical usesClinical uses

(1) Depression(1) Depression Endogenous depression (Endogenous depression ( 内源性抑郁内源性抑郁 ), ), melancholic depression (melancholic depression ( 更年期抑郁更年期抑郁 ), ), etc.etc.

(2) Enuresis ((2) Enuresis ( 遗尿遗尿 ))

(3) Anxiety, panic disorder ((3) Anxiety, panic disorder ( 惊恐障碍惊恐障碍 ) and ) and obsession (obsession ( 强迫症强迫症 ))


3. 3. Adverse effectsAdverse effects(1) Antimuscarinic effects(1) Antimuscarinic effects dry mouth, constipation, intraocular pressure increase, dry mouth, constipation, intraocular pressure increase,

blurred vision, urinary retention, blurred vision, urinary retention, ect.ect.

Contraindicated in prostatauxe and glaucomaContraindicated in prostatauxe and glaucoma

(2) CNS reactions(2) CNS reactions dizzy or deliriumdizzy or delirium （谵妄）（谵妄） , depression-mania (bipolar , depression-mania (bipolar

patients)patients)

(3) CVS reactions(3) CVS reactions Postural hypotension, sinus tachycardia, potential of Postural hypotension, sinus tachycardia, potential of

arrhythmiaarrhythmia


4. 4. Drug interactionsDrug interactions

(1) Plasma protein binding(1) Plasma protein binding displacement by phenytoin, aspirin, scopolamine, displacement by phenytoin, aspirin, scopolamine,

phenothiazines, phenothiazines, ect. ect.

(2) MAO inhibitors(2) MAO inhibitors potentiating the effects of TCA,potentiating the effects of TCA, contraindicated for combination with MAOIscontraindicated for combination with MAOIs

(3) Potentiating the effects of CNS depressant drugs(3) Potentiating the effects of CNS depressant drugs



Interaction of TCA with other types of drugs Interaction of TCA with other types of drugs


Other tricyclic antidepressantsOther tricyclic antidepressants

amitriptylineamitriptyline (( 阿米替林阿米替林 ))

clomipramineclomipramine (( 氯米帕明、氯丙咪嗪氯米帕明、氯丙咪嗪 ))

doxepindoxepin (( 多塞平多塞平 ))


NE reuptake inhibitors NE reuptake inhibitors ((NRIsNRIs)) Selective norepinephrine reuptake inhibitsSelective norepinephrine reuptake inhibits rapid actionsrapid actions weaker sedative, anticholinergic and hypotensive effectsweaker sedative, anticholinergic and hypotensive effects

desipramine desipramine (( 地昔帕明地昔帕明 ))

maprotiline maprotiline (( 马普替林马普替林 ))

nortriptyline nortriptyline (( 去甲替林去甲替林 )) protriptylin protriptylin (( 普罗替林普罗替林 ))

amoxapine amoxapine (( 阿莫沙平阿莫沙平 ))


Selective 5-HT reuptake inhibitorsSelective 5-HT reuptake inhibitors Selective serotonin reuptake inhibits (SSRIs)Selective serotonin reuptake inhibits (SSRIs) weaker sedative effectsweaker sedative effects with anti-anxiety effectswith anti-anxiety effects

fluoxetine fluoxetine (( 氟西汀，百氟西汀，百忧忧解解 ))

paroxetine paroxetine (( 帕罗西汀帕罗西汀 ))

sertraline sertraline (( 舍曲林舍曲林 ))


5-HT/NE reuptake inhibitors5-HT/NE reuptake inhibitors Mixed serotonin/norepinephrine reuptake inhibits Mixed serotonin/norepinephrine reuptake inhibits

(SNRIs)(SNRIs) rapid action rapid action less affinity with receptors less affinity with receptors higher safetyhigher safety

venlafaxine venlafaxine (( 文拉法辛文拉法辛 ))

milnacipram milnacipram (( 米那普仑米那普仑 )) lofepramine lofepramine (( 洛夫帕明洛夫帕明 ))

B.B. Antidepressant Drugs Antidepressant DrugsNoradrenergic and specific serotonergic Noradrenergic and specific serotonergic

antidepressantantidepressant (NaSSA) (NaSSA) mirtezapine mirtezapine (( 米氮平米氮平 ))

blockingblocking presynaptic (auto- or hetero-) presynaptic (auto- or hetero-) 22 receptor receptor on both on both

norepinephrine and serotonin (5-HT) presynaptic axonsnorepinephrine and serotonin (5-HT) presynaptic axons

- increasing NE and 5-HT release- increasing NE and 5-HT release;; stimulating postsynaptic stimulating postsynaptic 11 receptors receptors on serotonergic cell bodieson serotonergic cell bodies

- increasing the firing rate of serotonergic neurons- increasing the firing rate of serotonergic neurons potently blocking postsynaptic 5-HTpotently blocking postsynaptic 5-HT2A2A, 5-HT, 5-HT2C2C and 5-HT and 5-HT33

receptors receptors – attenuating 5-HT– attenuating 5-HT2C2C-mediated anxiety-mediated anxiety

The net outcome of these effects is increased noradrenergic The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, activity together with specific increased serotonergic activity, especially at 5-HTespecially at 5-HT1A1A receptors receptors

5-HT neuron firing 5-HT neuron firing

Blocking 5-HTBlocking 5-HT22, ,

5-HT5-HT33 receptors receptors

MirtazapineMirtazapine::

NE release NE release

5-HT 5-HT release release

5-HT5-HT1A1A ;; 5-HT5-HT2/32/3

NE & 5-HT release NE & 5-HT release


Monoamine oxidase inhibitors Monoamine oxidase inhibitors ((MAOIsMAOIs))

selective for central MAO-B, less selective for enteric selective for central MAO-B, less selective for enteric MAO-A; MAO-A;

used in treatments of depression (non-sensitive to used in treatments of depression (non-sensitive to TCAs) and Parkinson diseaseTCAs) and Parkinson disease

phenelzinephenelzine (( 苯乙肼苯乙肼 ): non-selective): non-selective

selegilineselegiline (( 司来吉兰司来吉兰 ): also used in Parkinson disease): also used in Parkinson disease

C.C. Antimanic Drugs Antimanic Drugs

Lithium carbonateLithium carbonateCarbamazepine Carbamazepine ChlorpromazineChlorpromazineOther related antiepileptic Other related antiepileptic

and antipsychotic drugs and antipsychotic drugs


1. 1. Pharmacological effects and clinical usesPharmacological effects and clinical uses

Mood-stabilizing agentMood-stabilizing agent

(1) Inhibiting NE and DA release(1) Inhibiting NE and DA release

(2) Interfering phosphatidylinositol (PI) metabolism(2) Interfering phosphatidylinositol (PI) metabolism

Lithium carbonate Lithium carbonate 碳酸锂碳酸锂

2. 2. Adverse effectsAdverse effects

Related to the serum concentration of LiRelated to the serum concentration of Li++

0.8 – 1.5 mmol/L:0.8 – 1.5 mmol/L: therapeutic leveltherapeutic level 1.6 – 2.0 mmol/L:1.6 – 2.0 mmol/L: GI reactionsGI reactions > 2.0 mmol/L:> 2.0 mmol/L: CNS toxicityCNS toxicity

Monitoring serum concentration of LiMonitoring serum concentration of Li++ if if possiblepossible


(1) Side effects(1) Side effects Nausea, vomiting, abdominal pain, diarrhea, Nausea, vomiting, abdominal pain, diarrhea,

sedation, finger tremor, polyuria, sedation, finger tremor, polyuria, etc.etc.

(2) Acute intoxication(2) Acute intoxication Mental confusion, coma, hyperreflexia, gross tremor, Mental confusion, coma, hyperreflexia, gross tremor,

dysarthria, seizures, kidney failure, death, dysarthria, seizures, kidney failure, death, etc.etc.

(3) Others (3) Others Benign thyroid enlargement, renal damageBenign thyroid enlargement, renal damage


D. Anxiolytic drugsD. Anxiolytic drugs

1. Benzodiazepines 1. Benzodiazepines see details in Ssee details in Sedative-Hypnotic Drugsedative-Hypnotic Drugs

2. Buspirone2. Buspirone （丁螺环酮）（丁螺环酮）

5-HT5-HT1A 1A receptor selective partial agonist, lowering receptor selective partial agonist, lowering

5-5-HT releaseHT release Fewer sedative, hypnotic, memory-deficient effectsFewer sedative, hypnotic, memory-deficient effects No cross tolerance to benzodiazepines, and less No cross tolerance to benzodiazepines, and less

potential of dependencepotential of dependence

drugs used in the treatment of psychological disorders §antipsychotic drugs §antidepressant and...

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