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Anxiety disordersLife time
prevalenceSymptoms Drug Other Prognosis
GAD 5.1% Non specific Anxiety
SSRI(+ benzo)
CBT 65-75%recover
PD 3.5% Recurrentpanic
SSRI Alprazolam
Exposure 25-45%improve
PHOBIA(specific)
11.3% Specificstimulant
Possibly BZto allowexposure
Exposure Reductioncommon butloss rare
PHOBIA(social)
13.3% Socialsituation
SSRI CBT 35-75%relapse ondrugwithdrawal
OCD 2.5% Repetitiveirrational
SSRICI
CBTsurgery
60% improvewithin 1 year
PTSD 1-3% Sequel totrauma
TCA, SSRI,MAOI
CBT
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Anxiety disorders: important comments
DSM IV provides detailed classification characteristics. Clinical trials demonstrate that benzodiazepines and all
classes of antidepressant are valuable in many of sub-classes (at appropriate dose).
Clinical opinion and usage varies significantly but NICEguidelines now available for GAD and Panic Disorder.
Distinct interventions are often patient specific ordetermined by patient preference.
CBT valuable and may produce significantimprovement in GAD.
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Generalized Anxiety Disorder
Excessive anxiety or worry occurring more days thannot for at least 6 months
Anxiety or worry is associated with 3 or more of thefollowing symptoms:
restlessness, keyed up or on-edge easily fatigued difficulties with concentration irritability muscle tension sleep disturbance
Symptoms cause clinically significant distress
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Occurrence of GAD
Lifetime prevalence about 5.1%
Onset can occur throughout life
Women are about twice as likely to seek helpthan men
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GAD: management The interventions that have evidence for the
longest duration of effect are, in descendingorder:
Psychological therapy (cognitive behaviouraltherapy, CBT)
Pharmacological therapy (SSRI)
Self-help (bibliotherapy use of written material tohelp people understand, and learn to deal with,their psychological problems)
www.nice.org.uk/CG022
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GAD: current therapy
The benzodiazepines are effective and provide rapidrelief but should not normally be used for longer than2-4 weeks: concern about their potential withdrawalsymptoms has limited their use
SSRIs (TCAs and MAOIs) provide similar relief atappropriate dose
Current therapy is SSRI plus benzodiazepine duringinitial 3-4 weeks to control initial exacerbation ofsymptoms and provide immediate relief.Benzodiazepine then slowly withdrawn with SSRIremaining.
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ANXIOLYTICS Drugs that decrease anxiety
Opiates Barbiturates Alcohol Buspirone Benzodiazepines SSRIs Beta-blockers
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History of anxiolytics First anxiolytic know to man was alcohol Bromide salts popular at the turn of this
century but produced CNS toxicity Barbiturates (diethylbarbituric acid)
introduced in 1903
Meprobamate introduced in 1955 Benzodiazepines introduced in 1960
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Anxiolytic benzodiazepines
N
N
Cl
NHCH 3
N
N
Cl
CH 3O
N
N
N
NH 3 C
Cl
N
N
Cl
HO
OH
N
N
N
Br
HO
N
N
Cl
HO
COOK
N
N
Cl
CH 3O
O
O
H 3 C
N
N
Cl
HO
OH
Cl
KetazolamDiazepam
Alprazolam
Lorazepam Oxazepam
O
Bromazepam Chlordiazepoxide Clorazepate
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Correlationbetween
binding siteaffinity andtherapeutic
dose
A v e r a g e
t h e r a p e u t
i c d o s e
m o
l / d a y
1
10
100
1000
1 10 100 1000
Affinity for benzodiazepine site, K i (nM)
triaz
clnfnz
lor
diaz nit
flr brm
oxzcdp
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The behavioural inhibition system
Behaviouralinhibition
system} {Inputs Outputs
signals of punishment behavioural inhibition
increment in arousal
increased attentioninate fear stimuli
novel stimuli
signals of non-reward
Anti-anxiety drugsimpair function
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The reticular formation and the limbic system
Evidence from behavioural studies, and theirmanipulation with brain lesions and pharmacologicalintervention, is consistent with the notion that thebehavioural inhibition system is anatomicallyassociated with the reticular formation and the limbicsystem
It is argued that the the brain stem reticular formation is activated by exteroceptive stimuli which are filteredand passed to the limbic circuit consisting of thefornix, cingulate gyrus, mamillary bodies,hypothalamus, amygdala and hippocampus
It is the mismanagement of these inputs which result
in inappropriate anxiety
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Neurophysiology of Anxiety
Sympathetic
activation
Flight
Amygdala
Limbic system andcortex
BehaviouralInhibition
System AvoidanceCaution
GABA neurones inhibit allthese sites
5-HT has complexinvolvement at most sites
Perception of being anxious
PAG
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Benzodiazepines All potentiate GABA by acting on the BDZ site
on the GABA A/Cl - channel macromolecule
So inhibit the anxiety systems
Differences mainly due to different half-lives
Very selective for their receptors, no problemside-effects due to non-selectivity
Example: Diazepam
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Other properties of Benzodiazepines
Sedation Anti-epileptic Amnesia: failure of transfer from
working to long-term memory. Due toinhibition of forebrain cholinergicneurones
Can cause impulsivity and loss ofinhibitions due to suppression of theBehavioural Inhibition System
Dependence risk (4th year)
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Problems with The Barbiturates
The barbiturates have a low therapeutic index (LD50 /ED 50 between 3:1 and 30:1) while this ratio forthe benzodiazepines is in excess of 300:1
The barbiturates cause marked respiratory
depression and are fatal in overdose. This is not thecase for the benzodiazepines Barbiturates show rapid tolerance and are dangerous
in withdrawal where convulsions are frequently found;not so for benzodiazepines
Barbiturates induce liver microsomal enzymes andthus modify the blood level of other drugs; thebenzodiazepines do not induce liver enzymes
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Alternate anxiolytics: I There is now significant evidence that all classes of
antidepressant are useful in the treatment of manysub-classes of anxiety disorder. SSRIs are currentlymost popular
They have distinct side-effect profiles, of which youmust be aware (see below)
Individual patients may prefer, or respond better to acertain class; thus multiple trials with a patient is notuncommon: ensure that appropriate criteria arefollowed in transferring from one medication toanother
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Alternate anxiolytics
N
N
NNN
H 3 C
O
H 2 NO
O NH 2
O
N
N
Cl
OOH
Buspirone
Meprobamate
Hyroxyzine
(5-HT 1A receptor agonist)
(Barbiturate-like)
(Sedative antihistamine)
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Importance of 5-HT systems in anxiety
Increasing evidence has been accumulatedfor the importance of 5-HT in the anxiety. In
addition to the use of imipramine (the tertiaryamine) in the treatment of anxiety, twoadditional classes of drugs are findingincreasing popularity in the effective control of
several classes of anxiety disorders: 5-HT 1A receptor agonists S elective S erotonin Reuptake Inhibitors
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Distribution of 5-HT 1A receptors
differentiallabelling incortical layers
heavy labellingin the amygdala
heavy labellingin hippocampus
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Buspirone is a 5-HT 1A agonist ; it does notinteract with benzodiazepine site. It has adistinct pharmacodynamic profile - it is notanti-convulsant or sedative. The onset ofthe anxiolytic effects of buspirone aredelayed - they appear after 3-4 weeks of
therapy.
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Anxious phenotype of the 5HT 1A receptorknockout mouse
All mice in which the 5HT 1A receptor gene hasbeen deleted show an anxious phenotype
These animals only appeared to me moreanxious under conditions of high stress
The knockout animals exhibit disturbances in the
GABA A receptor a 1 and a 2 subunit expressionin the amygdala
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Which action of Buspirone causes its anxiolyticeffect?
1.Postsynaptic agonist increases transmission through5-HT1A receptors
immediate effect that continues
2.3.Presynaptic down-regulator
effect 1 wears off in 3 weeks due toreceptor down-regulation leaves 5-HT neurones less regulated(so more responsive?) delayed effect that matches onset ofaction
Presynaptic agonist at cell-body autoreceptorsso inhibits 5-HT transmissionby reducing firing and releasebut immediate effectthat wears off
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Other alternate anxiolytics The -blockers are useful in the treatment of
performance anxiety (propranolol is the drug ofchoice)
Sedative antihistamines (hydroxyzine anddiphenhydramine) can be useful in the treatment ofanxiety, particularly in patients with dermatologicaldisorders
Barbiturates and meprobamate are now rarely usedas anxiolytics.
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Co-morbidity of anxiety and depression
Anxiety
Panicdisorder
MajorDepression
x 9.4
x 5.2 (phobic)(phobic) x 2.6
x 26.5
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Panic attack Panic attacks are characterised by a discrete period of
intense fear or discomfort in which the symptomsdevelop abruptly and peak within 10 minutes:
palpitations or accelerated heart rate, sweating, trembling orshaking
sensations of shortness of breath or smothering, feeling ofchoking, chest pain or discomfort nausea or abdominal distress, feeling dizzy, lightheaded or
faint derealisation or depersonalization, feeling of losing control or
going crazy, fear of dying numbness or tingling sensations, chills or hot flushes
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Panic disorder
Panic disorder is defined as four or more panicattacks in a period of 4 weeks
Lifetime prevalence of 3.5%
Most frequently occurs for the first time in early 20s
Women are more prone than men to suffer frompanic disorder (5:2)
Patients with panic disorder frequently developagoraphobia (95% of cases)
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Panic disorder with or withoutagoraphobia: management
The interventions that have evidence for thelongest duration of effect, in descending orderare:
Psychological therapy (cognitive behavioural therapy,CBT)
Pharmacological therapy (SSRI) Self-help (bibliotherapy use of written material to
help people understand, and learn to deal with, their
psychological problems)
www.nice.org.uk/CG022NICEguideline
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Pharmacological intervention inpanic disorder
Although panic disorder is classified with the anxietydisorders, only one benzodiazepine, alprazolam, isapproved for its treatment. However, allbenzodiazepines are effective but high doses arerequired and their therapeutic effectiveness is slowerthan in GAD.
The condition is frequently, and effectively treated withantidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs) tricyclic antidepressants monoamine oxidase inhibitor, phenelzine The response time is slower than for GAD
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Obsessive compulsive disorder
Characterised by repetitive fruitless physicalactivity e.g. washing of hands
Intrusive and repetitive thoughts that causedistress
NICE guidelines were introduced for OCD and
body dysmorphic disorder in 2005: CG031
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Intervention in OCD
CBT offered to alleviate the condition
If the patient is unable to effectively engage in CBT orthere is no adequate response an SSRI is introduced
Clomipramine may be used as an alternative if thepatient has previously responded to this intervention;note the cardiotoxicity of this drug
TCAs in general are not recommended
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Treatment of other anxiety disorders
Simple phobia (fear of insects etc): treat withbehaviour therapy but if immediate help is required(must travel by air) benzodiazepines can be used
Social phobia (fear of being scrutinized in public): -blockers as the symptoms are peripheral rather thancentral (propranolol drug of choice)
Post-traumatic stress disorder: antidepressants
NICE guidelines for PTSD were introduced in 2005: CG026
Alcohol withdrawal is best treated with thebenzodiazepines