• It is an emotional state commonly caused by the perception of real or perceived
danger that threatens the security of an individual.
• It is an uncomfortable feeling of apprehension or fear coupled with sensations of
• If anxiety is excessive or interferes with functioning, it is considered a pathologic
What IS ANXIETY…?
Differencebetween anxiety and fear
Fear is a response to a known, external, definite or non-conflictual threat
Anxiety is a response to a threat that is unknown, internal,vague or conflictual
•In general, anxiety disorders are a group of heterogeneous illnesses that
Develop before age 30 years,
Common in women,
Individuals with social issues,
Those with a family history of anxiety and depression
•The clinical picture of mixed anxiety and depression is much more common than
an isolated anxiety disorder.
•Generalized Anxiety Disorder:
GAD is unrealistic or excessive anxiety and worry about a number of events or activities.
Panic disorder begins as a series of unexpected (spontaneous) panic attacks involving an
intense, terrifying fear similar to that caused by life-threatening danger.
•Social anxiety disorder:
SAD is characterized by an intense, irrational, and persistent fear of being negatively
evaluated or scrutinized in at least one social or performance situation.
Presence of either obsessions and/or compulsions that are severe enough to cause marked
distress, to be time-consuming or to cause significant impairment in social or occupational
•Post-Traumatic Stress Disorder
Person must have witnessed, experienced, a situation that involved definite or threatened
death or serious injury, or possible harm to themselves or others. The patient’s response to
the trauma includes intense fear, helplessness, or horror.
•GAD is a syndrome of ongoing unrealistic or excessive anxiety and worry about
many events or activities that the patient generally recognises as excessive and
inappropriate. The condition can be chronic and debilitating.
What is GAD..??
•Biological studies in GAD have found abnormalities
GABA-A receptor function.
• Several studies report decreased α2-adrenergic receptors in GAD patients, and this
is believed to represent downregulation of receptors in response to high
•Abnormally low levels of lymphocyte peripheral benzodiazepine receptors (PBRs)
have been reported
•GAD patients have also shown enhanced anxiety in response to CCK-4
administration compared with normal controls, suggesting an increased sensitivity of
the CCK system in GAD.
Decreased 5HT / Increased NE
Stimulation of the locus ceruleus
produces increased NE transmission
and a state of heightened arousal
that contribute to anxiety 10
Diagnostic Criteria for Generalized AnxietyDisorder
The diagnostic criteria for GAD require persistent symptoms for most days for at least 6 months
0–4: minimal anxiety
5–9: mild anxiety
10–14: moderate anxiety
15–21: severe anxiety
•seven-item scale (GAD-7) has shown reliability, validity, and
adequate sensitivity (89%) and specificity (82%)
General Approach to Treatment
Patients with GAD may be managed with psychotherapy, pharmacotherapy, or
both. The Patients with severe symptoms resulting in functional impairment
should receive anti-anxiety medication.
Among potential drug therapies
are all considered first-line treatments for GAD.
The goals of therapy for GAD are
•To acutely reduce the severity and duration of anxiety symptoms and restore
•The long-term goal in GAD is to achieve and maintain remission.
A primary consideration when choosing among these options is whether any
comorbid psychiatric conditions are present.
• Venlafaxine, duloxetine, and paroxetine are good initial choices for patients
with concurrent depression, which is common in GAD patients. They are also
preferred over benzodiazepines in patients with past or present alcohol or
•Another important consideration when selecting treatment for GAD is how fast
therapeutic effects are needed. Benzodiazepines reduce anxiety within a few
hours, whereas the antidepressants and buspirone have delayed onsets of
•Combination benzodiazepines-SSRI therapy during initial treatment of anxiety
disorders is well tolerated and may result in synergistic anxiolytic effects and
• Relaxation training
• Meditation exercises
Are often helpful in relieving anxiety and improving coping skills.
Cognitive therapy is aimed at identifying negative thought patterns that may
provoke or worsen anxiety and changing them to be more positive.
Combined cognitive-behavioral therapy (CBT) has been associated with significant
reductions in anxiety that are maintained over 6 to 12 months, as well as
decreased psychiatric comorbidity in GAD
•Considered first-line agents in the management of GAD.
• Venlafaxine extended-release, duloxetine, paroxetine, and escitalopram are
FDA-approved antidepressants for GAD.
•The antianxiety response of antidepressants is delayed by 2 to 4 weeks or longer.
•Acute response and remission rates are approximately 65% and 30%, respectively
•At initiation of treatment, antidepressants can themselves be anxiogenic—thus, an
initial dose, in conjunction with short-term treatment with a benzodiazepine, is
•Imipramine, has demonstrated efficacy in patients diagnosed with GAD with
or without comorbid depression.
•Psychic symptoms of tension, apprehension, and worry have been more
responsive to TCAs
•Treatment should be initiated at one-quarter or one-half the usual dose,
which should be titrated slowly
SSRI’s (selective serotonin reuptake inhibitors)
•Paroxetine, escitalopram ,fluvoxamine, Sertraline, and citalopram
efficacious in reducing symptoms of GAD.
•The number of dropouts was significantly lower in the group of patients
treated with SSRIs (18%) than TCAs (31%).
•Initial feeling of increased anxiety so dose should be increased slowly
•If discontinuation needed taper over several weeks.
SNRI’s ( combination serotonin/norepinephrine reuptake inhibitors)
•In patients with comorbid depression, effective for both disorders
•Therapeutic benefit in both short term and long term use
•Improvement after first one week of treatment.
•Improves social functioning.
•Significant increases in blood pressure are not usually seen within the
dosage range used for GAD (75–225 mg/day), clinically significant
hypertension is only induced at doses >300 mg/day
Duloxetine (Cymbalta) is indicated for the treatment of:
•Major Depressive Disorder
•Diabetic Peripheral Neuropathic Pain
•Generalized Anxiety Disorder (GAD)
•Both duloxetine and venlafaxine are reported to cause insomnia, probably because
of the increase in NE levels.
•The percentage of patients who experience insomnia increases with higher doses.
About 10-16% of patients (duloxetine) and 16-24% (venlafaxine) experience
•Duloxetine would be the suitable antidepressant in patients with hypertension.
•Duloxetine is associated with a small increase in heart rate (tachycardia), even
in low doses
•Serious and potentially fatal hepatotoxicity has been reported with duloxetine.
Postmarketing reports have described isolated cases of liver failure, including
fatalities, which were possibly related to duloxetine. Most cases were in people
with past or current risk factors for liver injury, including alcohol abuse.
5-HT neurons depicting the impact of
an SSRI on 5-HT neurotransmission.
• A 5-HT1a partial agonist that lacks anticonvulsant, muscle relaxant, sedative-
hypnotic, motor impairment, and dependence properties.
• Considered a second-line agent for GAD because of inconsistent reports of
efficacy, delayed onset of effect, Takes 2 to 3 weeks to show effect
• Useful in patients with comorbid depression
• It has a mean t1/2 of 2.5 hours, and it is dosed 2 to 3 times daily.
• Side effects include dizziness, nausea, and headaches.
• Effective in treating cognitive rather than somatic symptoms also muscle
relaxation & sense of well being
• Mirtazapine - causes an especially low incidence of anxiety as a side effect
attributed to its serotonin receptor type-2 blocking activity.
•Nefazodone -anxiolytic effects in patients with GAD but it was associated
with several cases of severe hepatotoxicity.
• An antihistamine( blocks H1 & muscarinic receptors).
• Often used to reduce the anxiety that is associated with anesthesia and surgery.
•The weak anxiolytic property is thought to be a direct consequence of their
ability to produce sedation.
•which binds to the α2δ subunit of voltage-gated calcium channels to reduce
nerve terminal calcium influx, acts on “hyper-excited” neurons.
•Produces anxiolytic effects similar to lorazepam, alprazolam, and venlafaxine
•Improves both somatic and psychic symptoms
•Dose should be tapered over a week on discontinuation.
Advantages of antidepressants over benzodiazepines in treating GAD include
•Superior efficacy for cognitive symptoms such as excessive worry
•Better coverage for common comorbid disorders depression & other anxiety
•Lack potential for abuse and dependence
•Disadvantage: withdrawal syndrome on abrupt discontinuation.
Benzodiazepine (BZD) Therapy
• Effectively reduce somatic symptoms but limited effect on decreasing worry. Psychological
and Physical Dependence.
• The dose must be individualized, and duration of therapy usually should not exceed
4 months. Some patients require longer treatment.
• The elderly have an enhanced sensitivity to BZDs
• It is theorized that BZDs ameliorate anxiety through potentiation of GABA activity.
• Benzodiazepines bind on the GABAA receptor at the α1,α2,α3,& α5 subunits in combination
with a β subunit and the γ2 subunit.
• The anxiolytic effects of benzodiazepines are mediated at the α2 site while sedative effects
result from binding at the α1 subunit.
• By enhancing the effect of GABA on GABAA receptors decrease firing in the locus ceruleus,
thus reducing distribution of norepinephrine to the forebrain and amygdala
• The most common side effect of BZs is CNS depression. Tolerance usually develops to this
effect. Other side effects are disorientation, psychomotor impairment, confusion,
aggression, excitement, and anterograde amnesia
After BZDs are abruptly discontinued, three events 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
•Withdrawal is the emergence of new symptoms and a worsening of preexisting
•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.
•A BZD with a long-t1/2 (e.g., diazepam, clonazepam) may be substituted for a
drug with a short-t1/2 (e.g., lorazepam, oxazepam, alprazolam). The substituted
drug should be given for several weeks before gradual tapering begins.
•Adjunctive use of imipramine, valproic acid, or buspirone can help to reduce
withdrawal symptoms during the BZD taper 29
Positive and negative effects of drugs used to treat anxiety