ANXIETY DISORDERS

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ANXIETY DISORDERS
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Definition Anxiety is an unpleasant feeling of
apprehension or fearful concern. It can be
-Normal, reasonable and expected response to
a stressful situation or perceived danger
(adaptive purposes) or It may be
-An excessive, irrational state that signifies a
mental disorder (maladaptive)
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• Clinical subtypes of anxiety include
• Generalized anxiety disorder (GAD)
• Panic disorder (PD)
• Obsessive-compulsive disorder (OCD)
• Posttraumatic stress disorder (PTSD)
• Social phobia (SP)

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Epidemiology The prevalence of anxiety
disorders in the general population is about
10-20 There is a high rate of co-morbidity with
depressive disorders. The overall female to
male ratio is nearly 21. The age of onset of
most anxiety disorders is in young adulthood
(twenties and thirties) The maximum prevalence
of generalized anxiety and agoraphobia-panic in
the general population is in the 50-64 year age
group.
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Pathophysiology Neurotransmitter systems
involved in anxiety generation include 1)
The GABAA-benzodiazepine receptor complex
2) The serotonin (5HT1A/5HT2C) receptor
group 3) The noradrenergic
system These brain receptor systems mediate the
effects of the three main classes of drugs used
for treating neurotic disorders
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Patients with anxiety disorders, particularly PD,
exhibit symptoms of peripheral autonomic
hyperactivity including Tremulousness,
palpitations, and hyperventilation According to
the noradrenergic model The autonomic nervous
system of patients with anxiety disorders becomes
oversensitive to various stimuli, responding
with excess amount of noradrenaline.
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GABA (Gamma-aminobutyric acid) is the major
inhibitory neurotransmitter Attenuation of the
effects of GABA causes Increased
arousal Enhanced memory Anxiety Restlessness Insom
nia Exaggerated reactivity (startle) Convulsions
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The indolamine neurotransmitter serotonin (5HT)
has been proposed to play a role in anxiety
disorders The hypothalamic-pituitary-adrenal
axis (HPA) also plays a role in anxiety
disorders Perceived threat or stress activates
the HPA axis and one of its components,
corticotrophin-releasing factor (CRF) Evidence
suggests that CRF is responsible for integrating
the endocrine, autonomic, and behavioral
responses of an organism to stress
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• Clinical presentation and diagnosis
• It is important to exclude organic causes such
  as
• Thyrotoxicosis
• Excessive use of stimulant drugs such as caffeine
• The possibility of alcoholism or withdrawal
  effects from benzodiazepines
• Unnecessary investigations should be avoided if
  possible
• It is also important to determine whether the
  anxiety is situational anxiety (usually last 2-3
  weeks) or an anxiety disorder

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• A variety of medical conditions may cause anxiety
  symptoms
• In this case the anxiety may be labeled as
  anxiety disorder due to a general medical
  condition
• Anxiety symptoms may be associated with almost
  all major psychiatric illnesses such as
• Schizophrenia
• Major depression
• Dysthymia
• Mania
• Delirium
• Dementia
• Substance-related disorders

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Medical disorders associated with anxiety
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Several pharmacologic agents are known to produce
anxious symptoms Anxiety associated with the use
of these agents is seen when they are abruptly
discontinued after chronic use Some
pharmacologic agents known to produce anxious
symptoms
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• Generalized Anxiety Disorder
• The essential feature of GAD is excessive and
  unrealistic worry about several life situations
  that has been present for 6 months or longer
• The anxiety must be accompanied by at least three
  of the following six symptoms
• Restlessness
• Fatigability
• Difficulty concentrating
• Irritability
• Muscle tension
• Disturbed sleep
• Many patients with GAD also experience somatic
  symptoms (e.g., headache, irritable bowel
  syndrome) and depressive symptoms

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Panic Disorder A Panic attack is a discrete
period of intense fear or discomfort that is
accompanied by at least four somatic or cognitive
symptoms
Panic attacks occur in the context of several
different anxiety disorders and it is separate
from the disorder
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• The essential criterion of Panic Disorder (PD)is
• Recurrent, unexpected panic attacks (without
  specific stimulus)
• Followed by at least one month of persistent
  concern with the possibility of experiencing
  further attacks,
• Worry about the possible implications or
  consequences of the episodes, or
• A significant change in the patients behavior
  secondary to the attacks

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• Obsessive-Compulsive Disorder
• The essential feature of OCD is recurrent
  obsessions or compulsions
• That cause marked distress,
• Are time consuming, or
• Interfere significantly, with normal occupational
  functioning, social activities, or relationships

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Posttraumatic Stress Disorder PTSD may develop
when a person experiences or witnesses an event
that involves actual or threatened death or
serious injury, or a threat to the physical
integrity of self or others As a response to the
event, the person reacts with intense fear,
helplessness, or horror Social Phobia SP is
characterized by a persistent fear of social or
performance situations in which embarrassment may
occur
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• TREATMENT
• Drugs provide only symptomatic treatment of
  anxiety and do not cure the underlying disorder
• They may temporarily help patients to cope with
  stress and provide a short-term cover
• This will allows time for more specific
  treatments to take effect
• Effective treatment in the long term is by
  non-pharmacological interventions including
• -Counseling
• -Psychotherapy
• -Behavioral and cognitive methods
• -Relaxation and anxiety management training

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Pharmacotherapy Commonly used antianxiety
medications include BZDs Buspirone ß-blockers TC
As MAOIs, SSRIs
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• Benzodiazepines
• Currently available BZD antianxiety agents are
• Alprazolam (Xanax)
• Chlordiazepoxide (Librium)
• Clonazepam (Rivotril)
• Diazepam (Valium)
• Lorazepam (Ativan)
• Oxazepam (Serax)
• Still the most commonly prescribed drugs for
  anxiety
• Have potent anxiolytic effects which are exerted
  at low doses that produce minimal sedation
• In subjects with low trait anxiety and in
  non-stressful conditions BZDs may paradoxically
  increase anxiety and impair psychomotor
  performance

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The major site of anxiolytic action is the limbic
system The effect is mediated by a primary
action at GABAA receptors, resulting in
enhancement of inhibitory GABA activity Secondary
suppression of noradrenergic and/or serotonergic
pathways may be of particular importance in
relation to anxiolytic effects The most common
indication for BZD therapy is GAD Alprazolam has
the efficacy of as an antipanic agent 2 to 6
mg/day usually is sufficient for most patients
with PD taking alprazolam
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The total daily BZD dosages in PD tend to be much
higher than those in GAD Patients experiencing
interdose symptom breakthrough switch from
alprazolam to clonazepam (anticonvulsant)
Clonazepam has longer half life Patients who do
not respond to one BZD may respond to another The
high-potency BZD are effective for SP, with onset
of response occurring within 2 weeks. Clonazepam
was reported to significantly improve patients
with long-term treatment in dose of 1.5 to 2
mg/day Alprazolam is another BZD considered
effective for SP at 3 mg/day.
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Choice of BZD in anxiety BZD can be valuable in
the short term management of anxiety because of
their anxiolytic efficacy and rapid onset of
action. Pharmacokinetic characteristics affect
the choice of an appropriate BZD Potent BZDs
such as lorazepam have been widely used for
anxiety disorders but are probably inappropriate.
Lorazepam is moderately rapidly eliminated and
needs to be taken several times daily.
Declining blood concentrations may lead to
inter-dose anxiety as the anxiolytic effect of
each tablet wears off.
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A slowly eliminated BZD such as diazepam is more
appropriate in most cases. Diazepam has a rapid
onset of action, and its slow elimination ensures
a steady blood concentration. It should be
prescribed in the minimal effective dosage to
avoid cumulative effects It can also be used as
a hypnotic, thus avoiding the need for a separate
hypnotic drug. Patients with hypoalbuminemia may
have greater free fraction of BZDs that are
highly protein bound. For these patients,
lorazepam or alprazolam would be a rational
choice because of its lower percentage of protein
binding.
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Patients should be started on low dosages and
titrated upward to the lowest effective dosage.
The anxiolytic use of BZDs should generally be
limited to short-term (2 weeks) or intermittent
use. Parenteral administration of lorazepam or
diazepam may occasionally be indicated for
severely agitated psychiatric patients.
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Profile of some drugs used in anxiety disorders
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Adverse effect of anxiolytic use
Tolerance Tolerance to the anxiolytic effects
of BZDs seems to develop more slowly than to the
hypnotic effects. Most patients reporting
initial drowsiness find that it wears off in a
few days while the anxiolytic effects remains for
some weeks. BZDs are usually no longer
effective in the treatment of anxiety after 1-4
months of regular use.
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Psychomotor impairment Long-term use of BZDs
results in psychomotor impairment and has adverse
effects on memory Many patients on long-term
BZDs complain of poor memory, and incidents of
shoplifting have been attributed to memory lapses
caused by BZDs use. Additive effects with other
CNS depressants including alcohol occur, and may
contribute to traffic and other accidents
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Disinhibition, paradoxical effects
Occasionally, BZDs produce paradoxical
stimulant effects. These effects are most
marked in anxious subjects and include
Excitement Increased anxiety
Irritability Outbursts of
rage Increased daytime anxiety can occur with
rapidly eliminated BZDs, such as lorazepam, and
is probably a withdrawal effect.
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• Affective reactions
• Chronic use of BZDs
• Can aggravate depression and provoke suicide in
  depressed patients
• Can cause depression in patients with no previous
  history of depressive disorder.
• Some patients on long-term BZDs complain of
  emotional anesthesia with inability to
  experience either pleasure or distress.
• In some patients, BZDs induce euphoria, and they
  are increasingly used as drug of abuse when taken
  in high doses or self administered intravenously

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Dependence The greatest drawback of chronic BZD
use is the development of drug dependence. The
regular use of therapeutic doses of BZDs for more
than a few weeks can give rise to
dependence Withdrawal symptoms on cessation of
drug use occur in over 40 of patients.
Abuse Patients with a history of alcohol or
other drug abuse are at greatest risk of becoming
BZD abusers. Diazepam, followed by alprazolam
and lorazepam, has been judged to have the
greatest potential for abuse among the BZDs.
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BZD withdrawal Abrupt withdrawal in dependent
subjects is dangerous, and can induce acute
anxiety, psychosis or convulsion. BZDs should
be discontinued gradually, by one-eighth to
one-fourth of the total dosage every few weeks to
allow careful monitoring and to reduce the risk
of withdrawal or rebound. Substituting a
long-half-life BZD for a short to
intermediate-half-life drug before downward
tapering may reduce the severity of withdrawal
symptoms
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Drug interactions with the BZD antianxiety agents
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Buspirone Buspirone has a structure and mode of
action completely different from that of BZDs It
has mixed agonist/antagonist action at
serotonergic receptors that are thought to be
involved in anxiety It has anxiolytic effects
comparable with those of BZDs, but it is without
sedative/hypnotic, anticonvulsant or muscle
relaxant effects A major disadvantage is that
anxiolytic effects are delayed for up to 3 weeks,
and in some patients buspirone produces dysphoria
and may actually increase anxiety Concurrent use
of buspirone and MAOIs is not recommended because
blood pressure may increase
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Buspirone may displace digoxin from plasma
proteins. Serum haloperidol may be increased by
buspirone. Unlike BZDs, buspirone does not
produce -Physical dependence -Withdrawal
symptoms -Abuse -Lacks interaction with alcohol
Buspirone does not usually alleviate anxiety
associated with BZD withdrawal. Buspirone is
recommended for short term use only and its place
in the treatment of anxiety is doubtful at
present.
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Antidepressant drugs A number of tricyclic
(TCAs) and other antidepressants have additional
sedative or anxiolytic effects They appear to
be as effective as BZDs in GAD and superior in
agoraphobia. The efficacy of imipramine in
treating PD is now well established, and recently
clomipramine has been reported to be superior to
imipramine in PD treatment. Also, clomipramine
is well-documented to be effective in treating
OCD. The TCAs have the most solidly established
efficacy in treating core intrusive PTSD
symptoms.
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• Imipramine and amitriptyline have produced
  positive results in treating veterans with PTSD.
• TCAs are also of value in depressive states
  associated with anxiety and in anxiety/depression
  associated with BZD withdrawal
• Selective serotonin reuptake inhibitors (SSRIs)
  and monoamine oxidase inhibitors (MAOIs) are also
  effective in phobic states and panic disorders.
• A disadvantage of all these drugs is
• Their slow onset of action which may be delayed
  for 2-4 weeks
• They may initially exacerbate anxiety symptoms.
• For this reason it is advisable to start with
  small doses.

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• The mode of action of these drugs is thought to
  be
• An initial increase in central serotonergic and
  noradrenergic activity
• This may cause further anxiety
• Followed by a down-regulation of adrenergic and
  serotonergic receptors, accounting for the
  delayed anxiolytic effect.
• Another disadvantage of antidepressants is that
• Some are toxic in overdose
• Have many adverse effects including
  anticholinergic actions, cardiovascular actions,
  especially in the elderly
• Drug interactions, and interaction with certain
  foods.

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• Antidepressants more suitable for long term use
  than BZDs, and can be continued for several
  months.
• They are often effective in low to moderate doses
  and do not cause cognitive impairment.
• Some patients have difficulty in stopping these
  drugs because of withdrawal symptoms, which
  include
• Rebound excessive cholinergic activity
• Increased anxiety or depression.
• Withdrawal should therefore be carried out
  gradually.

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ß adrenoceptor blockers Some somatic symptoms of
anxiety such as palpitations and tremor are due
to excessive sympathetic activity acting on
peripheral ß adrenoceptors These symptoms can be
alleviated by ß adrenoceptor blockers such as
propranolol These drugs, when used in small doses
which do not induce hypotension, can be of value
in acutely stressful situations or panic attacks
where physical symptoms dominate the picture They
have little effect on subjective symptoms If used
regularly, withdrawal should be gradual to
prevent rebound tachycardia and return of
palpitations.
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Antipsychotic drugs Some antipsychotic drugs
such as chlorpromazine and haloperidol have
sedative and anxiolytic effects They may, on
occasion, be of short term use in severe anxiety
disorders associated with panic. They have a
rapid onset of action (within 1 hr) but should be
used in minimal dosage and only short-term since
they carry a risk of dyskinesias and other
adverse effects. Anxious patients may have
withdrawal problems after regular use. The
growing tendency to prescribe these drugs as
alternatives to BZDs is to be deprecated.
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Rational use of drugs in anxiety It is clear
that drugs do not provide a long-term solution
for anxiety. In acute anxiety states, often
precipitated by stress, short-term BZDs may help
to cop with the immediate situation as they have
high efficacy and a rapid onset of action.
Diazepam is probably the drug of choice. A
single dose may be sufficient, and it should not
be continued regularly for more than 1 or 2
weeks It can be given intermittently and
intermittent courses can be repeated if necessary
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Potent, short acting BZDs such as alprazolam and
lorazepam should be avoided BZDs are not
recommended in bereavement because their amnesic
actions may interfere with subsequent
adjustment If longer-term treatment is required
in GAD, anxiety/depression or phobic states,
sedative TCAs or SSRIs are preferred These drugs
are efficacious, can be used for several months
and do not interfere with non-pharmacological
treatment MAOIs are effective in panic and
phobic disorders
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• ß adrenoceptor blockers are effective in
  controlling somatic symptoms such as palpitations
  and tremor
• The most effective long-term treatment of anxiety
  is by psychological methods, which can include
• Self-help groups
• Counseling
• Behavioral and cognitive techniques
• Anxiety management training
• Psychotherapy

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Common therapeutic problems in the management of
anxiety
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