Anxiety Disorders

Desalegn Feyissa (B.Pharm., MSc, RPh, Assistant Professor of Clinical

Pharmacy)

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Introduction
• anxiety is the feeling of fear that is disproportionate to the
actual threat

• It shares features of excessive fear and related behavioral

disturbances.

• Its symptoms are irrational or experienced at a level of

severity that impairs functioning.

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 Cont…
• The anxiety disorders differ from one another
– in the types of objects or situations that induce fear, anxiety, or
avoidance behavior and the associated cognitive ideation.

• Anxiety disorders differ from developmentally normative fear

by being excessive or persisting beyond appropriate periods.
– e.g., typically lasting 6 months or more
Epidemiology
• Anxiety disorders are the most commonly occurring
psychiatric disorders.

• In general, anxiety disorders are a group of

heterogeneous illnesses that develop before age 30 years

• Anxiety disorders are more common in:

– Women (2:1)
– individuals with social issues and
– those with a family history of anxiety and depression

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Etiology
• Hypotheses on the etiology of anxiety disorders are
based on interactions between a combination of
factors including
– Vulnerability (e.g., genetic predisposition) and
– Stress (e.g., occupational and traumatic experience).

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Pathophysiology
Noradrenergic model
• This model suggests that the autonomic nervous system of
anxious patients is hypersensitive and overreacts to various
stimuli.

• The locus ceruleus may have a role in regulating anxiety, as it

activates norepinephrine release and stimulates the sympathetic
and parasympathetic nervous systems.

• Drugs with anxiolytic or antipanic effects (e.g.,

benzodiazepines) inhibit LC firing, decrease noradrenergic
activity, and block the effects of anxiogenic drugs.
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Cont…
GABA receptor model
• GABA is the major inhibitory neurotransmitter in the CNS.
• Abnormalities of GABA inhibition may lead to increased
response to stress
• Anxiety symptoms may be linked to under activity of
GABA systems or down-regulated central BZ receptors.
• Many antianxiety drugs target the GABAA receptor.

• Benzodiazepines (BZs) enhance the inhibitory effects of

GABA.

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Cont…
5-HT model
• 5-HT is primarily an inhibitory neurotransmitter
• Abnormalities in serotonergic functioning may play a role
in anxiety disorder
• It is postulated that greater 5-HT activity reduces NE
activity in the LC
• SSRIs acutely increase 5-HT levels by blocking the
Serotonin reuptake transporter (SERT) to increase the
amount of 5-HT available post-synaptically and are
efficacious in blocking the manifestations of panic and
anxiety.
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Neuro-imaging studies
• amygdala, anterior cingulate cortex (ACC) and
insula play a crucial role in the pathophysiology of
anxiety.

• In GAD there is an abnormal increase in the brain's

fear circuitry, as well as increased activity in the
prefrontal cortex,
• which appears to have a compensatory role in
reducing GAD symptoms.

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Cont…
• Patients with panic have abnormalities of midbrain
structures, including the periaqueductal gray matter
(PAG)

• Patients with SAD have greater activity in the amygdala

and insula, structures linked to negative emotional
responses.

• Both pharmacotherapy and psychotherapy decreases

cerebral blood flow in the amygdala, hippocampus, and
surrounding cortical areas in patients with SAD
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Classification of Anxiety
Disorders:DSM-5
• Separation anxiety disorder
• Selective mutism
• Specific phobia
• Social anxiety disorder (social phobia)
• Panic disorder
• Agoraphobia
• Generalized anxiety disorder
• Substance/medication induced anxiety disorder
• Anxiety disorder due to another medical condition
• Other specified anxiety disorder
• Unspecified anxiety disorder
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 Social Anxiety Disorder
(Social Phobia)
• The individual is fearful or anxious about or avoidant of
social interactions and situations that involve the
possibility of being scrutinized. These include:
– social interactions such as meeting unfamiliar people,
– situations in which the individual may be observed eating or
drinking, and
– situations in which the individual performs in front of others.

• The cognitive ideation is of being negatively evaluated by

others, by being embarrassed, humiliated, or rejected, or
offending others
 Panic Disorder
• The individual experiences recurrent unexpected panic
attacks and is persistently concerned or worried about
having more panic attacks or changes his or her behavior
in maladaptive ways because of the panic attacks
– e.g., avoidance of unfamiliar locations

• Panic attacks are abrupt surges of intense fear or intense

discomfort that reach a peak within minutes,
accompanied by physical and/or cognitive symptoms.
Generalized Anxiety Disorder (GAD)
• The key features are
– persistent and excessive anxiety and worry about
various domains, including work and school
performance, that the individual finds difficult to
control.
Clinical Manifestation: GAD
• The diagnostic criteria require persistent symptoms
most days for at least 6 months.
• The anxiety or worry must be about a number of
matters and is accompanied by at least three
psychological or physiologic symptoms
• The median age at onset is 30 years
• The course of illness is chronic, with multiple
spontaneous exacerbations and remissions.
• There is a high percentage of relapse and a low rate of
recovery.
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Clinical Manifestation: Panic
Disorder
• Symptoms usually begin as a series of unexpected
panic attacks.

• These are followed by at least 1 month of persistent

concern about having another panic attack.

• During an attack, there must be at least four physical

symptoms in addition to psychological symptoms.

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Cont…
• Symptoms reach a peak within 10 minutes and
usually last no more than 20 or 30 minutes.

• Many patients eventually develop agoraphobia,

which is avoidance of specific situations (e.g.,
crowded places, bridges) where they fear a panic
attack might occur.

• Patients may become homebound

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Cont…

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Clinical Manifestation: SAD
• The essential feature of SAD is an intense, irrational,
and persistent fear of being negatively evaluated in a
social or performance situation.
• Exposure to the feared situation usually provokes a
panic attack.
• The fear and avoidance of the situation must interfere
with daily routine or social/occupational functioning.
• It is a chronic disorder with a mean age of onset in
the teens (75% of them within 8-15 years)

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Cont…

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Diagnosis
• Evaluation of the anxious patient requires
– a complete physical and mental status examination;
– appropriate laboratory tests; and
– a medical, psychiatric, and drug history.

• Anxiety symptoms may be present in several major

psychiatric illnesses (e.g., mood disorders,
schizophrenia and substance withdrawal).

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Desired Outcome
• The goals of treatment of SAD are to
– reduce the physiologic symptoms and phobic avoidance,
– increase participation in desired social activities, and
– improve quality of life

• The desired outcomes of treatment of GAD are:

– to reduce severity, duration, and frequency of the symptoms
and to improve overall functioning.
– The long-term goal is minimal or no anxiety or depressive
symptoms, no functional impairment, and improved quality
of life.
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Cont…
• The goals of therapy of panic disorder include:
– a complete resolution of panic attacks,
– marked reduction in anticipatory anxiety and phobic fears,
and
– resumption of normal activities.

* After treatment, 40% to 50% of patients continue to have

occasional panic attacks and phobic avoidance

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Cont…

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Treatment
Generalized Anxiety Disorder (GAD)
• For patients with GAD, non-pharmacologic
modalities include
– short-term counseling
– stress management
– cognitive therapy
– Meditation
– supportive therapy and
– exercise

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Cont…
• GAD patients should be educated to avoid caffeine,
stimulants, excessive alcohol, and diet pills.

• Cognitive behavioral therapy (CBT) is the most

effective psychological therapy for GAD patients

• Most patients with GAD should have psychological

therapy, alone or in combination with antianxiety
drugs.

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Cont…

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Antidepressants
• Efficacious for acute & long-term management of GAD.

• Considered the treatment of choice for long-term

management of chronic anxiety, especially in the
presence of depressive symptoms.

• Antianxiety response requires 2 to 4 weeks.

• Acute response and remission rates are approximately

65% and 30%, respectively.
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Cont…
• Imipramine may be used when patients fail to respond to
SSRIs
• Common side effects of the SSRIs are:
– ,nausea, ejaculation disorders, decreased libido, dry mouth,
insomnia and fatigue.
• TCAs commonly cause:
– sedation, orthostatic hypotension, anticholinergic effects,
and weight gain.
• TCAs are very toxic on overdose.

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Cont…
• Initially, anxious patients should be monitored once to
twice weekly for
– reduction in anxiety symptoms
– improvement in functioning and
– side effects.

• The Visual Analog Scale may assist in the evaluation of

drug response

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Benzodiazepine Therapy
• The BZs are the most frequently prescribed drugs for the
treatment of acute anxiety

• All BZs are equally effective anxiolytics, and most of

the improvement occurs in the first 2 weeks of therapy.

• They are considered to be more effective for somatic and

autonomic symptoms of GAD,
– antidepressants are considered more effective for the
psychic symptoms (e.g., apprehension and worry).

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Cont…
• It is theorized that BZs ameliorate anxiety through
potentiation of GABA activity.
• The dose must be individualized.
• Some patients require longer treatment.
• The elderly have an enhanced sensitivity to BZs and may
experience falls when on BZ therapy.
– Intermediate- or short-acting BZs are preferred for chronic
use in the elderly and those with liver disorders because of
minimal accumulation

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Pharmacokinetics
• Diazepam and Clorazepate have high lipophilicity and
are rapidly absorbed and distributed into the CNS.
– They have a shorter duration of effect after a single dose as they
are rapidly distributed to the periphery.
– IM diazepam and chlordiazepoxide should be avoided because
of variability in rate and extent of absorption.

• Lorazepam and oxazepam are less lipophilic and have a

slower onset but a longer duration of action.
– They are not recommended for immediate relief of anxiety.
– IM lorazepam provides rapid and complete absorption.

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Adverse Events
• The most common side effect of BZs is CNS depression.
• Other side effects are:
– Disorientation or Confusion
– psychomotor impairment
– Aggression
– Excitement
– Antero-grade amnesia

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Benzodiazepine Discontinuation
• After BZs are abruptly discontinued 3events can occur:
– Rebound symptoms are an immediate, but transient,
return of original symptoms with an increased
intensity compared with baseline.
– Recurrence or relapse is the return of original
symptoms at the same intensity as before treatment.
– Withdrawal is the emergence of new symptoms and a
worsening of preexisting symptoms.
• The onset of withdrawal symptoms is within 24 to 48 hours after
discontinuation of short elimination half-life BZs and 3 to 8 days
after discontinuation of long elimination half-life drugs.

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Cont…
• Discontinuation strategies include the following:
– A 25% per week reduction in dosage until 50% of the dose
is reached, then dosage reduction by one-eighth every 4 to
7 days.

– If therapy exceeds 8 weeks, a taper over 2 to 3 weeks is

recommended, but if duration of treatment is 6 months, a
taper over 4 to 8 weeks should ensue.

– Longer durations of treatment may require a 2- to 4-month

taper.

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Cont…

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Dosing and Administration
• Initial doses should be low, and dosage adjustments can
be made weekly

• Treatment of acute anxiety generally should not exceed 4

weeks.

• BZs can be given as needed, and if several acute courses

are necessary, a BZ-free period of 2 to 4 weeks should
be implemented between courses.

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Buspirone Therapy
• Buspirone is a 5-HT1A partial agonist
– lacks anticonvulsant, muscle relaxant, sedative-hypnotic,
motor impairment, and dependence-producing properties.

• It is considered a second-line agent for GAD because of

– inconsistent reports of efficacy
– delayed onset of effect and
– lack of efficacy for comorbid depressive and anxiety
disorders (e.g., panic disorder or SAD).

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Cont…
• It is the agent of choice in patients:
– who fail other anxiolytic therapies or
– with a history of alcohol or substance abuse

• It is not useful for situations requiring rapid antianxiety

effects or as-needed therapy.

• It has a mean t 1 /2 of 2.5 hours, and it is dosed two to

three times daily.

• Side effects include: dizziness, nausea, and headaches.

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Drug Interactions
• Buspirone may increase haloperidol levels and elevate
blood pressure in patients taking MAOIs.

• Verapamil, itraconazole, and fluvoxamine can increase

buspirone levels

• Rifampin reduces buspirone blood levels by 10-fold.

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Dosing and Administration
• Starting dose: 7.5 mg bid
• Dose range: 15-60 mg/day
• Buspirone doses can be titrated in increments of 5 mg/day
every 2 or 3 days as needed.
• The onset of anxiolytic effects requires 2 weeks or more;
maximum benefit may require 4 to 6 weeks.

• When switching from a BZ to buspirone, the BZ should

be tapered slowly

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 Cont…

Fig: Algorithm for the

pharmacotherapy of (GAD)
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Treatment
Panic Disorder: General Therapeutic Principles
• A meta analysis showed that SSRIs, TCAs and CBT are
similarly effective

• FDA approved for this indication

– Alprazolam, clonazepam, sertraline, paroxetine and
venlafaxine

• SSRIs are first-line agents, but BZs are the most

commonly used drugs for panic disorder.

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Cont…
• Most patients without agoraphobia improve with
pharmacotherapy alone, but if agoraphobia is present,
CBT typically is initiated concurrently.
• Patients treated with CBT are less likely to relapse than
those treated with imipramine alone.
• For patients who cannot or will not take medications,
CBT alone is indicated,
– as it is associated with improvement in 80-90% of patients
short-term and 75% of patients at 6-month follow-up.

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Cont…
• Patients must be educated to avoid caffeine, drugs of
abuse, and stimulants.

• Antidepressants, especially the SSRIs, are preferred in

elderly patients and youth.

• The BZs are second line in these patients because of

potential problems with disinhibition.

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Cont…

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Antidepressants
• Stimulatory side effects (e.g., anxiety, insomnia, jitteriness,
irritability) can occur in TCA - and SSRI -treated patients.

• This may affect compliance and hinder dose increases.

• Low initial doses and gradual dose titration may eliminate

these effects

• Imipramine blocks panic attacks within 4 weeks, but

maximal improvement, including reduced anticipatory anxiety
and anti-phobic response, requires 8 to 12 weeks.
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Cont…
• About 25% of panic patients discontinue TCAs because
of side effects.
• All SSRIs eliminate panic attacks in 60% to 80% of
patients.
• The antipanic effect requires 4 weeks, and some patients
do not respond until 8 to 12 weeks.
• Low initial doses of SSRIs and gradual titration to the
antipanic dose are required to avoid stimulatory side
effects.

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Benzodiazepines
• BZs are second-line agents except when rapid response is
essential.
• They should not be used as monotherapy in panic
disorder patients with a history of depression or alcohol
or drug abuse.
• BZs are often used concomitantly with antidepressants in
the first weeks to offset the delay in onset of antipanic
effects.
• About 60-80% of panic patients respond to BZs, but
relapse rates of ≥ 50% are common despite slow drug
tapering.
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Cont…
• Alprazolam and clonazepam are the most frequently
used of the BZs and are well accepted by patients.

• Therapeutic response typically occurs in 1 to 2 weeks.

• With alprazolam, the duration of action may be as little as

4 to 6 hours with breakthrough symptoms between
dosing.
– The use of extended-release alprazolam or clonazepam
avoids this problem.

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Dosing and Administration
• The starting dose of clonazepam is 0.25 mg twice daily,
with a dose increase to 1 mg by the third day.
– Increases by 0.25 to 0.5 mg every 3 days to 4 mg/day can
be made if needed.

• The starting dose of alprazolam is 0.25 to 0.5 mg three

times daily (or 0.5 mg once daily of alprazolam ER),
– slowly increasing over several weeks to an ideal dose.
– Most patients require 3 to 6 mg/day.

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Cont…
• Usually patients are treated for 12 to 24 months before
discontinuation (over 4 to 6 months) is attempted.
• Many patients require long-term therapy.

• Successful maintenance with single weekly doses of

fluoxetine has been described.

• Patients with panic disorder should be seen every 2

weeks during the first few weeks to adjust medication
doses based on symptom improvement and to monitor
side effects.
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Cont…
• Once stabilized, they can be seen every 2 months.

• The Hamilton Rating Scale for Anxiety (score  7 - 10)

can be used to measure anxiety

• Sheehan Disability Scale (with a goal of  1 on each

item) can be used to measure for disability.

• During drug discontinuation, the frequency of

appointments should be increased.

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Fig: Algorithm for the pharmacotherapy of
panic disorder.

Cont…

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Treatment
Social Anxiety Disorder (SAD)
• SAD patients often respond more slowly and less
completely than patients with other anxiety disorders.

• After improvement, at least 1 year of maintenance

treatment is recommended to maintain improvement and
decrease the rate of relapse.

• Long-term treatment may be needed for patients with

unresolved symptoms, comorbidity, an early onset of
disease, or a prior history of relapse.

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Cont…
• CBT and pharmacotherapy are considered equally
effective in SAD, but CBT can lead to a greater
likelihood of maintaining response after treatment
termination.

• Even after response, most patients continue to experience

more than minimal residual symptoms.

• CBT and social skills training are effective in children

with SAD.

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Cont…
• Evidence supports the efficacy of SSRIs and SNRIs in
children 6 to 17 years of age.

• Individuals up to 24 years of age should be closely

monitored for increased risk of suicidality

• Response rates of SSRIs in SAD ranged from 50% to

80% after 8 to 12 weeks of treatment.
• Paroxetine, sertraline, and venlafaxine ER are
approved for treatment of generalized SAD and are first-
line agents.
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Cont…

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Fig: Algorithm for the pharmacotherapy of
generalized social anxiety disorder.

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