Gangguan

Kecemasan/Ansietas

HARI RONALDO TANJUNG

DEPT. FARMAKOLOGI
FAKULTAS FARMASI
UNIVERSITAS SUMATERA
UTARA

Edvard Munch, 1896 –

“Anxiety”
Ansietas adalah emosi normal
dalam merespon ancaman and
motivator yg kuat
Ansietas tingkat ringan hingga
sedang meningkatkan kemampuan
untuk mengatasi, reaksi menjadi
lebih cepat, Pemahaman lebih baik
dan response lebih sesuai.
Dalam keadaan setimbang,
kecemasan yg moderat/sedang
adalah hal yg baik.
Bagaimanapun, ansietas kronis yg
berat akan menurunkan
kemampuan untuk merencanakan,
membuat penilaian dengan akurat,
memadukan informasi – mereka
dapat menghilangkan kemampuan
berpikir dan beraksi.
 Gangguan kecemasan adalah sekelompok
kondisi kejiwaan yang melibatkan kecemasan
yang berlebihan.

Sumber kegelisahan/kecemasan ini tidak

selalu diketahui atau diakui, yang dapat
menambah penderitaan yang dirasakan.
Jenis Gangguan Kecemasan

• Panic Disorder
• Generalized Anxiety Disorder
• Post Traumatic Stress Disorder
• Social Anxiety Disorder
• Specific Phobia
• Obsessive Compulsive Disorder
(OCD)
Generalized Anxiety Disorder (GAD)
 Patients with GAD suffer from severe worry or
anxiety that is out of proportion to situational
factors.
 Must last most days for at least 6 months
 Described as “worriers” or “nervous” that

uncontrollable
GAD

 Symptoms include:
◦ Muscle tension
◦ Restlessness
◦ Insomnia
◦ Difficulty concentrating
◦ Easy fatigability
◦ Irritability (lekas marah)
◦ Persistent anxiety (rather than discrete panic
attacks)
GAD Diagnostic Criteria
 Excessive anxiety and worry that occurs more
days than not for 6 months
 Difficult to control the worry
 3 out of 6 symptoms
 Anxiety caused significant distress or

impairment in function
 Not attributed to another organic cause
GAD Epidemiology
 5% prevalence in community samples
 2:1 female/male ratio
 Age of onset is frequently in childhood or

adolescence
 Chronic but fluctuating course of illness

(worsened during stressful periods)

GAD Treatment
 Cognitive Behavioral Therapy
 Other Psychotherapies
 Pharmacotherapy

◦ Antidepressants
◦ Benzodiazepines
◦ Buspirone
Pharmacological Treatment of GAD
• First‐line
Recommended daily doses: Antidepressants
• Escitalopram 10‐20mg Venlafaxine 75‐225 mg
• Paroxetine 20‐50 mg Duloxetine 60‐120 mg
• Sertraline 50‐150 mg
• Second‐line
– Benzodiazepines when patient has no history of dependency; may combine with
antidepressants for first 2‐4 weeks
– Pregabalin 150‐600 mg; Imipramine 75‐200 mg
• Others
– Hydroxyzine 37.5‐75 mg– effective in trials for acute anxiety, but ADRs limit use
– Buspirone 15‐ 60 mg– indicated for GAD, but efficacy results were inconsistent
• Treatment resistance
– Augmentation of SSRI with atypical antipsychotic (quetiapine, risperidone or
olanzapine)
– Quetiapine effective as monotherapy, but not FDA approved for anxiety because of
metabolic and cardiac risks associated with chronic use

WFSBP Guidelines for the Pharmacological Treatment of Anxiety, Obsessive Compulsive ,

and Post-Traumatic Stress Disorders- First Revision (2008)
Panic Disorder
Diagnostic Criteria for Panic Disorder
• Presence of at least 2 unexpected panic attacks characterized by at
least 4 of the following somatic or cognitive symptoms, which
develop abruptly and peak within 10 minutes:
• Cardiac, sweating, shaking, SOB or choking (tersedak) , nausea,
dizziness, depersonalization, fear of loss of control, fear of dying,,
chills or hot flashes
• The attacks are followed by one of the following for 1 month:
• Persistent concern about having another attack
• Worry about consequences of the attack
• Significant change in behavior because of the attack
• May occur with or without agoraphobia (takut akan keramaian,
public places)

Diagnostic and Statistical Manual of Mental Disorders‐IV‐TR, 2000.

Differential Diagnosis of Panic
Disorder
 Not due to another anxiety disorder
 Not due to effects of a general medical
condition
◦ Cardiovascular disease
◦ Pulmonary disease
◦ Neurological disease
◦ Endocrine disease
◦ Drug intoxication or withdrawal
◦ Other (lupus, infections, heavy metal poisoning,
uremia, temporal arteritis)
Panic disorder epidemiology
 -1-3% of general population; 5-10% of
primary care patients ---Onset in teens or
early 20’s
 -Female:male 2-3:1
Panic disorder epidemiology
 30-50% have agoraphobia
◦ avoidance of situations where escape would be
difficult
 50-60% have lifetime major depression
◦ one third with current depression
 20-25% have history of substance
dependence
Panic Disorder: Treatment
 About 80% of patients will respond to
treatment
 Antidepressant medications are effective
◦ Serotonin reuptake inhibitors (SSRI) are first line
therapy
◦ Tricyclic antidepressants (TCA) and monoamine
oxidase inhibitors (MAOI’s) are also used.
Panic Disorder: Treatment
 Sedative-Hypnotics: benzodiazepines are
ideally used in the short term before an
antidepressant has had time to work
 Cognitive Behavioral Therapy (CBT): helps

patients overcome a learned pattern of

catastrophically misinterpreting the physical
symptoms associated with panic attacks.
Pharmacological Treatment of Panic Disorder

First‐line:
Recommended daily doses
• Citalopram 20‐60 mg Paroxetine 20‐60 mg
• Escitalopram 10‐20 mg Sertraline 50‐150 mg
• Fluoxetine 20‐40 mg Venlafaxine 75‐225 mg
• Fluvoxamine 100–300 mg
Second‐line
– Imipramine 75‐250 mg , clomipramine 75‐250 mg
– Benzodiazepines when no history of dependency; may combine with
antidepressants for first 2‐4 weeks for more rapid response and to limit
ADRs
• Alprazolam 1.5‐8 mg/day Diazepam 5‐20 mg/day
• Clonazepam 1‐4 mg/day Lorazepam 2‐8 mg/day

WFSBP Guidelines for the Pharmacological Treatment of Anxiety, Obsessive

Compulsive , and Post-Traumatic Stress Disorders- First Revision (2008)
Social Anxiety Disorder
 Marked fear of one or more social or
performance situations in which the person is
exposed to the possible scrutiny of others and
fears he will act in a way that will be
humiliating
 Exposure to the feared situation almost
invariably provokes anxiety
 The person recognizes the fear is excessive
 The feared situation is avoided or endured
with distress
 The avoidance, fear or distress significantly
interferes with their routine or function
SAD epidemiology
 12% of general population
 Age of onset teens; more common in women.

Stein found half of SAD patients had onset of

sx by age 13 and 90% by age 23.
 Causes significant disability
 Increased depressive disorders

Incidence of social anxiety disorders and the consistent risk for secondary depression in the first three decades of life. Arch
Gen Psychiatry 2007 Mar(4):221-232
Social Anxiety Disorder Treatment
• Early detection and treatment is important
• Because of the nature of the illness, patients
are reluctant to seek treatment
• Pharmacological and nonpharmacological
therapy both effective
 Social Anxiety Disorder
Nonpharmacologic Treatment
• CBT
– Change negative thoughts patterns
– Repeated exposure to feared situation
– Social skills training
– 12‐16 weekly sessions, each 60‐90 minutes
– Workbook with homework exercise
– Clinical improvement within 6‐12 weeks
– Long term gains
Pharmacological Treatment of SAD

First‐line
Recommended doses:
• Escitalopram 10‐20 mg Fluoxetine 20‐40 mg
• Fluvoxamine 100‐300 mg Sertraline 50‐150 mg
• Paroxetine 20‐50 mg Venlfaxine 75‐225 mg
Second‐line
– Imipramine 75‐200 mg
– Clonazepam 1.5‐8 mg/day, when patient has no history of dependency;
may combine with antidepressants for first 2‐4 weeks
Treatment resistance
– Addition of buspirone to an SSRI effective in one open study; buspirone
not effective as monotherapy.
– Phenelzine

WFSBP Guidelines for the Pharmacological Treatment of Anxiety, Obsessive

Compulsive , and Post-Traumatic Stress Disorders- First Revision (2008)
Post Traumatic Stress Disorder
 The person was exposed to a traumatic event
and both of the following were present:
◦ The event involved actual or threatened death or
serious injury to self or others
◦ The person’s response involved intense fear,
helplessness or horror
 Duration of symptoms is >1 month and cause
significant distress or impairment in
functioning
Types of Trauma
 Sexual abuse
 Rape
 Physical abuse
 Severe motor vehicle accidents
 Robbery/mugging
 Terrorist attack
 Combat veteran
 Natural disasters
 Being diagnosed with a life threatening illness
 Sudden unexpected death of family/friend
 Witnessing violence (including domestic violence)
 Learning one’s child has life threatening illness
Subtypes of PTSD
• Acute – symptom duration of < 3 months
• Chronic – symptom duration of > 3 months
• Delayed onset – symptoms begin > 6 months
after the traumatic event
Acute Treatment After Traumatic Event
• Symptoms should diminish over the first few
weeks
• Social support is critical
• 4‐5 sessions of time‐limited psychotherapy
during the first month reduces the rates of
PTSD by at least 50%
Diagnosis of PTSD
 Symptoms must be > one month duration
and include:

◦ Re-experiencing symptoms
◦ Avoidance symptoms
◦ Emotional numbing (mati rasa)
◦ Hyperarousal symptoms (gairah
berlebihan)
Re-experiencing Symptoms
 There are recurrent, intrusive thoughts of the
event (can’t not think about it)
 Dreams (nightmares) about the event
 Acting or feeling the event is recurring, or
sense of living the event (flashbacks)
 Psychological or Physiological Distress upon
exposure to reminders or cues of the event.
Avoidance/Numbing Symptoms
 Avoid thoughts, feelings, places or people that
arouse memories of the event
 Being unable to recall important parts of the event
 Decrease interest in activities
 Feeling detached or estranged from others
 Decreased range of affect
 Sense of foreshortened future
Hyperarousal Symptoms
 Patient experiences at least two of the
following:
◦ Insomnia (falling or staying asleep)
◦ Irritability or outbursts of anger
◦ Decreased concentration
◦ Hypervigilance
◦ Increased/exaggerated startle (terkejut) response
Epidemiology of PTSD
 Prevalence is 1% in the general population,
and can be as high as 25% in those who have
experienced trauma
 In combat veterans, prevalence is 20%
 Very high prevalence in women who are

victims of sexual trauma

PTSD Treatment
 Psychotherapies
◦ Exposure-based cognitive behavioral therapy
◦ Psychotherapy aimed at survivor anger, guilt and
helplessness (victimization)
 Pharmacological treatment targets the
reduction of prominent symptoms
◦ SSRI’s are first line therapy
◦ Atypical antipsychotics are being increasingly
used
Pharmacotherapy of PTSD

First‐line
Recommended doses/day:
• Fluoxetine 20‐40 mg Paroxetine 20‐40 mg
• Sertraline 50‐100 mg Venlafaxine 75‐300 mg
– Prazosin may be more effective in combat‐related PTSD
Second‐line therapies
– TCAs : amitriptyline, imipramine 75‐200 mg
– Mirtazapine 30‐60 mg
– Risperidone 0.5‐6 mg
– Lamotrigine (study doses ranged from 50‐500 mg/day)
– Nefazodone (effective in small, controlled trial in male combat
veterans)
Treatment resistance
– Venlafaxine, prazosin, quetiapine + venlafaxine, gabapentin + SSRI

WFSBP Guidelines for the Pharmacological Treatment of Anxiety, Obsessive

Compulsive , and Post-Traumatic Stress Disorders- First Revision (2008)
Obsessive-Compulsive Disorder
 Obsessions: recurrent, intrusive, unwanted
thoughts (i.e. fear of contamination)

 Compulsions: behaviors or rituals aimed at

reducing distress or preventing a dreaded
event (i.e. compulsive handwashing)
OCD Symptoms
 Recurrent obsessions and/or compulsions are
severe enough to consume more than one
hour/day
 Person recognizes the obsession as a

“product of his/her own mind”, rather than

imposed from the outside, and that they are
unreasonable or excessive
 The obsessions are “ego-dystonic” (not

enjoyable for the ego), as opposed to “ego-

syntonic” (the ego likes it)
Common Obsessions
 Contamination
 Repeated doubts
 Order
 Aggressive or horrific images
 Sexual/pornographic imagery
 Scrupulosity (ketelitian)
Obsessions and Common
Compulsive Responses
 Contamination: cleaning, hand washing, showering
 Repeated doubts: checking, requesting or
demanding reassurances from others, counting
 Order: checking, rituals, counting
 Aggressive or horrific images, checking, prayers,
rituals
 Sexual/Pornographic imagery: prayer/rituals
Epidemiology of OCD
 Lifetime prevalence is 2-3% in the general
population
 Mean age of onset is mid-twenties, although
men may develop symptoms earlier
 Less than 5% of patients develop disease after
age of 35 years
 Chronic course, stress can exacerbate
symptoms
OCD Treatment
 Serotonin reuptake inhibitors
 Clomipramine, a serotonergic tricyclic

antidepressant
 Psychotherapy: exposure and response

prevention
Pharmacotherapy of OCD

First‐line
Recommended doses/day
• Escitalopram 10‐20 mg Fluoxetine 40‐60 mg
• Fluvoxamine 100‐300 mg Paroxetine 40‐60 mg
• Sertraline 50‐200 mg

Second‐line‐ typically reserved until after failure with 2 SSRIs

– Clomipramine 75‐250 mg; equally effective as SSRIs but
less well‐tolerated

Treatment resistance
– Intravenous clomipramine (not FDA approved) was more
effective than oral clomipramine
– SSRI + antipsychotic (haloperiodol, quetiapine, olanzapine,
risperidone) more effective than SSRI alone
Goals of Therapy in OCD

• Marked clinical improvement, recovery, and full remission

• Decrease symptom frequency and severity, improve the patient’s
functioning, and help the patient improve QOL
• Enhance the patient’s ability to cooperate with care
• Anticipate stressors likely to exacerbate OCD and help the
patient develop coping strategies
• Minimize any adverse effects
• Educate the patient and family about OCD and its treatment.
• Reasonable treatment outcome targets include:
– less than 1 hour per day spent obsessing and performing
compulsive behaviors; no more than mild OCD‐related anxiety;
an ability to live with uncertainty; and little or no interference

of OCD with the tasks of ordinary living

OCD Duration of Therapy

• After response, patient should remain on

pharmacotherapy for at least 1‐2 years
• Medication should be tapered over an
extended period of time
– Decrease dose by 25% every 2 months
• Life‐long prophylaxis recommended after 2‐4
severe relapses or 3‐4 mild relapses
Specific Phobia
 Marked or persistent fear that is excessive
or unreasonable cued by the presence or
anticipation of a specific object or situation
◦ The person recognizes the fear is excessive or
unreasonable
◦ It interferes significantly with the persons routine
or function
Phobia Subtypes
 Animals or insects
 Natural environment– storms, water, heights
 Blood, injury, injection, medical procedure
 Situational flying, driving, enclosed places
 Having a phobia of a specific subtype increased the
chances of having another phobia within that
subtype
Epidemiology of Specific Phobias
 Lifetime prevalence is 10% of the population
 Age of onset varies with subtype

◦ Childhood onset for phobias of animals, natural

environments blood and injections
◦ Bimodal distribution (childhood and mid-twenties
for situational phobias
Specific Phobia Treatments
 Flooding-exposing the person to the feared
stimulus
 Exposure therapy works to desensitize the
patient using a series of gradual, self-paced
exposures to the phobic stimulus; uses
relaxation, hypnosis, breathing control and
other cognitive approaches
 Benzodiazepines or Beta blockers are useful
acutely
 Treatment Plan

• Patient preference
• Severity of illness
• Comorbidity
• Concomitant medical illness
• Complications like substance abuse or
suicide risk
• History of previous treatments
• Cost issues
• Availability of treatments in given area
Patient Education
 Patient Education

• Mechanisms underlying psychic and somatic

anxiety should be explained.
• Describe typical features of the disorder,
treatment options, adverse drug effects.
• Explain advantages and disadvantages of the
drug:
– Delayed onset of effect
– Activation syndrome or initial jitteriness
(kejang) with SSRIs/SNRIs
Duration of Drug Treatment
• Anxiety disorders typically have a waxing and
waning course.
• After treatment response, which often occurs
much later in PTSD and OCD, treatment
should continue for at least 12 months to
reduce the risk of relapse.
Dosing

• In RCTs, SSRIs and SNRIs have a flat response curve

with the exception of OCD
– 75% of patients respond to the initial (low) dose
– In OCD, the dose must usually be pushed to maximally
tolerated dosages
• In elderly patients, treatment should be started with
half the recommended dose or less to minimize adverse effects
• Patients with panic disorder are very sensitive to
serotonergic stimulation and often discontinue
treatment because of initial jitteriness
• Antidepressant doses should be increased to the
highest recommended level if the initial low or medium
dose fails
Dosing

• Controlled data on maintenance treatment are

scarce
– Continue the same dose as in the acute phase
• For improved compliance, administer
medications in a single dose if supported by
halflife data
• Benzodiazepine doses should be as low as
possible, but as high as necessary
• In hepatic impairment, dose should be adjusted
 Monitoring Treatment Efficacy
 • Use of symptom rating scales:
 – Panic and Agoraphobia Scale (PAS)
 – Hamilton Anxiety Scale (HAM‐A)
 – Liebowitz Social Anxiety Scale (LSAS)
 – Yale‐Brown Obsessive‐Compulsive Scale (Y‐BOCS)
 – Clinician‐Administered PTSD Scale (CAPS)
 • Scales are time‐consuming and require training
 • Clinical Global Impression (CGI) or specific
selfreport
 measures may suffice in busy settings
Treatment Resistance

• Many patients do not fulfill response criteria after initial

treatment
• Commonly used threshold for response is ≥ 50%
improvement in total score of commonly used rating scale
• Review diagnosis, assess for adherence, maximally tolerated
dosages, sufficient trial period, assess for comorbidities
. Change the dose or switch to another medication?
• If no response after 4‐6 weeks (8‐12 weeks in OCD or PTSD),
then switch medication
• If partial response, reassess in 4‐6 weeks
• Issue of switching vs. augmentation is debated by period,
experts and not clearly defined in literature
•
Screening questions for anxiety
disorders
 How ever experienced a panic attack? (Panic)
 Do you consider yourself a worrier? (GAD)
 Have you ever had anything happen that still
haunts you? (PTSD)
 Do you get thoughts stuck in your head that really
bother you or need to do things over and over like
washing your hands, checking things or count?
(OCD)
 When you are in a situation where people can
observe you do you feel nervous and worry that
they will judge you? (SAD)
Selective Serotonin Reuptake
Inhibitors (SSRIs)
First‐line drugs for all anxiety disorders
• Dose and education at initiation of therapy is important
– Restlessness, jitteriness, insomnia, headache in the first
few days/weeks of treatment may jeopardize compliance
– Lower starting doses reduces overstimulation
• Adverse effects include headache, fatigue, dizziness,
nausea, anorexia
• Weight gain and sexual dysfunction are long‐term concerns
• Discontinuation syndrome: paroxetine
• Anxiolytic effect is delayed 2‐4 weeks (6‐8 weeks in
PTSD, OCD)
Selective Serotonin Norepinephrine
Reuptake Inhibitors (SNRIs)
. Efficacy of venlafaxine and duloxetine in certain
anxiety disorders has been shown in controlled
studies
• Early adverse effects such as nausea, restlessness,
insomnia and headache may limit compliance
• Sexual dysfunction long‐term
• Modest, sustained increase in blood pressure may
be problematic
• Significant discontinuation syndrome with
venlafaxine occurs, even with a missed dose
• Antianxiety effects have latency of 2‐4 weeks
Crank up the serotonin
 Cornerstone of treatment for anxiety
disorders is increasing serotonin
 Any of the SSRIs can be used as can SNRIS
How to use them
 Start at ½ the usual dose used for
antidepressant benefit i.e citalopram at 10mg
rather than the usual 20mg
 WARN THEM THEIR ANXIETY MAY GET WORSE

BEFORE IT GETS BETTER!!

 May need to use an anxiolytic while initiating

and titrating the antidepressant

Tricyclic Antidepressants (TCAs)
. Efficacy in all anxiety disorders is well‐proven, except in SAD
– Imipramine, clomipramine have most evidence
• Adverse effects: initially increased anxiety, anticholinergic,
cardiovascular, sedation, impaired cognition, decreased
seizure threshold, elevated LFTs (clomipramine)
• Weight gain, sexual dysfunction are problematic long‐term
• Discontinuation syndrome
• Avoid in elderly elderly, patients with cardiovascular
disease, seizure disorders, and suicidal thoughts
• Second‐line agents because of adverse effects/toxicity
• Dosage should be titrated up slowly; onset of effect is 2‐6
weeks, longer in OCD
Monamine Oxidase Inhibitors
(MAOIs)
. Efficacy of phenelzine established in panic, SAD
and PTSD
• Last‐line agent for treatment resistance; used by
experienced psychiatrists
– Risk of adverse effects
– Life threatening drug and food interactions
• Patient education on dietary restrictions and
drug interactions imperative
• Give doses in the morning and mid‐day to avoid
overstimulation and insomnia
Benzodiazepines
. Anxiolysis begins in 30‐60 minutes after oral or
parenteral administration
• Safe and effective for short‐term use; maintenance
requires evaluation of risks vs. benefits
• Avoid in patients with history of substance or alcohol
abuse
• Most commonly used in combination with SSRI/SNRI
during first few weeks of therapy
• Guideline recommendations: Prescribe on scheduled,
not prn basis
• Not effective in depression
Hydrozyzine
. Commonly used in community setting;
anxiolytic effects that may be beneficial in
treating GAD
• There are controlled data supporting efficacy,
but up to 40% of patients report adverse
effects
• This agent was similar to buspirone in
anxiolytic effects in a short‐term trial
• Hydroxyzine is not associated with
dependence
Other Agents
PREGABALIN
. Not FDA‐ approved for anxiety, but used commonly
in Europe
. Effective in acute/long‐term GAD and a few trials of
SAD
. Typical doses of 300‐600 mg/day
. Onset of activity was evident after 1 week
. Adverse effects: dizziness, sedation, dry mouth,
psychomotor impairment
. Pregabalin was not associated with clinically
significant withdrawal symptoms when tapered over
1 week
ANTICONVULSANTS
. Not used in routine treatment of anxiety
disorders but may some utility as adjunctive
agents in some disorders.

. Carbamazepine, valproate, lamotrigine, and

gabapentin have shown efficacy in
preliminary studies for PTSD
Buspirone
- Beneficial only in GAD
- Advantages:
• Non‐sedating
• No abuse potential
- Disadvantages:
• No antidepressant effect for comorbid conditions
• Initial therapeutic effect delayed by 1‐2 weks, full
effects occurring over several weeks
• Ineffective in patients who previously responded
to benzodiazepines??
Buspirone
- Adverse effect:
Nausea, headache,dizziness, jitteriness and
dysphoria (initial).
- Dosing

Initial 5 mg tid up to maximum 60 mg/day

ATYPICAL ANTIPSYCOTICS
. Quetiapine was effective as monotherapy for
GAD
. Atypical antipsychotics have been used as
adjunctive agents for non‐responsive cases of
anxiety associate with OCD and PTSD
BETA‐ADRENERGIC BLOCKERS
. β ‐ blockers ( propanolol) reduce autonomic
anxiety symptoms such as palpitations,
tremor, blushing
. However, double‐blind studies have not
shown efficacy in any disorder
. Recommended for use in non generalized
SAD; given before a performance situation