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Anxiety Disorders

Rowa’ Al-Ramahi

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CLINICAL PRESENTATION

GENERALIZED ANXIETY DISORDER

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 illness has a gradual onset at an average age of 21 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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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. Symptoms reach a peak within 10 minutes and usually last no more than 20 or 30 minutes.

Up to 70% of 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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SOCIAL ANXIETY DISORDER

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.

In the generalized subtype, fear is of many social situations where embarrassment may occur. In the discrete or specific subtype, fear is limited to one or two situations (e.g., performing, public speaking).

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POSTTRAUMATIC STRESS DISORDER

In PTSD, exposure to a traumatic event causes immediate intense fear, helplessness, or horror.

Patients must have at least one reexperiencing symptom, three signs or symptoms of persistent avoidance of stimuli, and at least two symptoms of increased arousal. Symptoms from each category must be present longer than 1 month and cause significant distress or impairment.

PTSD can occur at any age, and the course is variable.

Most patients with PTSD meet criteria for another mental disorder, for example, about 80% have a concurrent depression or anxiety disorder or substance abuse or dependence.

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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 associated with medical illnesses or drug therapy.

Anxiety symptoms may be present in several major psychiatric illnesses (e.g., mood disorders, schizophrenia, organic mental syndromes, and substance withdrawal).

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DESIRED OUTCOME

GAD: 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.

Panic disorder: a complete resolution of panic attacks, marked reduction in anticipatory anxiety and phobic fears, elimination of phobic avoidance, 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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DESIRED OUTCOME

SAD: to reduce the physiologic symptoms and phobic avoidance, increase participation in desired social activities, and improve quality of life.

PTSD: to decrease core symptoms, disability, and comorbidity and improve quality of life and resilience to stress.

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TREATMENT

GENERALIZED ANXIETY DISORDER

For patients with GAD, nonpharmacologic modalities include psychotherapy, short-term counseling, stress management, cognitive therapy, meditation, supportive therapy, and exercise.

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, and most patients with GAD should have psychological therapy, alone or in combination with antianxiety drugs.However, CBT is not widely available.

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Kava kava is not recommended as an anxiolytic because of reports of lack of efficacy and hepatotoxicity.

Hydroxyzine is often used in primary care settings but it is considered a second line agent.

Pregabalin produced anxiolytic effects similar to lorazepam, alprazolam, and venlafaxine in acute trials. Sedation and dizziness were the most common adverse effects, and the dose should be tapered over 1 week upon discontinuation.

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The FDA has established a link between antidepressant use and suicidality (suicidal thinking and behaviors) in children, adolescents, and young adults 18 to 24 years old. All antidepressants carry a black box warning advising caution in the use of all antidepressants in this population, and the FDA also recommends specific monitoring parameters. The clinician should consult the FDA-approved labeling or the FDA website for additional information

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Antidepressants

Antidepressants are efficacious for acute and long-term management of GAD. They are 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.

SSRI, venlafaxine extended release & duloxetine, paroxetine, are effective in acute therapy with response rates of 60-80%.

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Imipramine may be used when patients fail to respond to SSRIs.

Common side effects of the SSRIs are somnolence, nausea, ejaculation disorders, decreased libido, dry mouth, insomnia, and fatigue.

Tricyclic antidepressants (TCAs) commonly cause sedation, orthostatic hypotension, anticholinergic effects, and weight gain. TCAs are very toxic on overdose.

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Benzodiazepine Therapy

The BZs are the most effective, safe & 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, while antidepressants are considered more effective for the psychic symptoms (e.g., apprehension and worry).

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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.

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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 than would be predicted on the basis of half-life, as they are rapidly distributed to the periphery.

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.

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IM diazepam and chlordiazepoxide should be avoided because of variability in rate and extent of absorption. IM lorazepam provides rapid and complete absorption.

Clorazepate, a prodrug, is converted to desmethyldiazepam in the stomach through a pH-dependent process that may be impaired by concurrent antacid use. Several other BZs are also converted to desmethyldiazepam, which has a long half-life and can accumulate, especially in the elderly and those with impaired oxidation.

Intermediate- or short-acting BZs are preferred for chronic use in the elderly and those with liver disorders because of minimal accumulation and achievement of steady state within 1 to 3 days.

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Adverse Events

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.

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Abuse, Dependence, Withdrawal, and Tolerance

Those with a history of drug abuse are at the greatest risk for becoming BZ abusers.

BZ dependence is defined by the appearance of a predictable withdrawal syndrome (i.e., anxiety, insomnia, agitation, muscle tension, irritability, nausea, malaise, diaphoresis, nightmares, depression, hyperreflexia, tinnitus, delusions, hallucinations, and seizures) upon abrupt discontinuation.

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Benzodiazepine Discontinuation

After BZs 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 before treatment.

Withdrawal is the emergence of new symptoms and a worsening of preexisting symptoms.

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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.

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.

Adjunctive use of carbamazepine can help to reduce withdrawal symptoms during the BZ taper.

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Drug Interactions

The combination of BZs with alcohol or other CNS depressants may be fatal.

Alprazolam dose should be reduced by 50% if nefazodone (Serzone) or fluvoxamine is added.

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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. Persistent symptoms should be managed with antidepressants.

BZs with a long t1/2 may be dosed once daily at bedtime and may provide nighttime hypnotic and anxiolytic effects the next day.

In the elderly, doses should be low, and short-elimination half-life agents chosen. Close monitoring is required for sedation & falls.

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Buspirone Therapy

Buspirone is a 5-HT1A partial agonist that 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). It is the agent of choice in patients who fail other anxiolytic therapies or in patients with a history of alcohol or substance abuse. It is not useful for situations requiring rapid antianxiety effects or as-needed therapy.

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It has a mean t1/2 of 2.5 hours, and it is dosed two to three times daily.

Side effects include dizziness, nausea, and headaches.

Drug InteractionsBuspirone may increase blood pressure in patients

taking a MAOI.

Verapamil, itraconazole, and fluvoxamine can increase buspirone levels, and rifampin reduces buspirone blood levels by 10-fold.

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Dosing and Administration

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.

Evaluation of Therapeutic Outcomes

Initially, anxious patients should be monitored once to twice weekly for reduction in anxiety symptoms, improvement in functioning, and side effects. The Hamilton Rating Scale & Sheehan disability scale may assist in the evaluation of drug response.

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PANIC DISORDER

A metaanalysis showed that SSRIs, TCAs, and CBT are similarly effective with 50-80% of patients responding.

Alprazolam, clonazepam, sertraline, paroxetine, and venlafaxine are FDA approved for this indication.

SSRIs are first-line agents, but BZs are the most commonly used drugs for panic disorder.

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.

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For patients who cannot or will not take medications, CBT alone is indicated.

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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AntidepressantsStimulatory 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 in 75% of patients, but maximal improvement, including reduced anticipatory anxiety and antiphobic response, requires 8 to 12 weeks.

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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.

Approximately 54% to 60% of patients became panic-free on venlafaxine extended release 75 mg or 150 mg

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BenzodiazepinesBZs 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.

Relapse rates of 50% or higher are common despite slow drug tapering.

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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 AdministrationThe 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 extended release), slowly increasing over several weeks to an ideal dose. Most patients require 3 to 6 mg/day.

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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.

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Evaluation of Therapeutic OutcomesPatients 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. Once stabilized, they can be seen every 2 months. Disorder severity scale (with a goal of 3 or less with no or mild agoraphobic avoidance, anxiety, disability or depressive symptoms) and the Sheehan Disability Scale (with a goal of less than or equal to 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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SOCIAL ANXIETY DISORDERSAD 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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CBT (exposure therapy, cognitive restructuring, relaxation training, and social skills training) 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.

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CBT and social skills training are effective in children with SAD. Evidence supports the efficacy of SSRIs and serotonin norepinephrine reuptake inhibitors in children 6 to 17 years of age. Individuals up to 24 years of age should be closely monitored for increased risk of suicidality.

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Response rates of SSRIs in SAD ranged from 50% to 80% after 8 to 12 weeks of treatment. Paroxetine, sertraline, extended release fluvoxamine and venlafaxine extended release are approved for treatment of generalized SAD and are first-line agents.

With SSRI treatment, the onset of effect is delayed 4 to 8 weeks, and maximum benefit is often not observed until 12 weeks or longer.

The TCAs are not effective for SAD.

Limited data suggest that citalopram is also effective for SAD, but that fluoxetine is not effective.

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SSRIs are initiated at doses similar to those used for depression. If there is comorbid panic disorder, the SSRI dose should be started at one-fourth to one-half the usual starting dose of antidepressants. The dose should be tapered slowly during discontinuation to decrease the risk of relapse.

Some patients unresponsive to SSRIs have improved with venlafaxine extended release. Response has been reported by week 3.

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BZs should be reserved for patients at low risk of substance abuse, those who require rapid relief, or those who have not responded to other therapies.

Clonazepam is the most extensively studied BZ for treatment of generalized SAD. It improved fear and phobic avoidance, interpersonal sensitivity, fears of negative evaluation, and disability measures. Adverse effects include sexual dysfunction, unsteadiness, dizziness, and poor concentration. Clonazepam should be tapered at a rate not to exceed 0.25 mg every 2 weeks.

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Gabapentin was effective for SAD, and onset of effect was 2 to 4 weeks. Pregabalin was superior to placebo at a dose of 600mg/d.

β-Blockers blunt the peripheral autonomic symptoms of arousal (e.g., rapid heart rate, sweating, blushing, and tremor) and are often used to decrease anxiety in performance-related situations. For specific SAD, 10 to 80 mg of propranolol or 25 to 100 mg of atenolol can be taken 1 hour before the performance. A test dose should be taken at home on a day before the performance to be sure adverse effects will not be problematic.

Incomplete response to a first-line agent may benefit from augmentation with buspirone or clonazepam.

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Phenelzine, an MAOI, is effective, but is reserved for treatment-resistant patients because of dietary restrictions, potential drug interactions, and adverse effects.

Patients with SAD should be monitored for symptom response, adverse effects, and overall functionality and quality of life. Patients should be seen weekly during dosage titration and monthly once stabilized. Patients should be asked to keep a diary to record symptoms and their severity. The clinician related Liebowitz Social Anxiety Scale and the patient-rated Social Phobia Inventory can be used to monitor severity of symptoms and symptom change.

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POSTTRAUMATIC STRESS DISORDER Immediately after the trauma, patients should receive

treatment individualized to their presenting symptoms (e.g., non-BZ hypnotic, short courses of CBT). Brief courses of CBT in close proximity to the trauma resulted in lower rates of PTSD.

If symptoms (e.g., hyperarousal, avoidance, dissociation, insomnia, depression) persist for 3 to 4 weeks and there is social or occupational impairment, patients should receive pharmacotherapy or psychotherapy, or both.

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Psychotherapies for PTSD include anxiety management (e.g., stress-inoculation training, relaxation training, biofeedback, distraction techniques), CBT, group therapy, hypnosis, psychodynamic therapies, and psychoeducation. Psychotherapy may be used in patients with mild symptoms, those who prefer not to use medications, or in conjunction with drugs in those with severe symptoms to improve response.

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The SSRIs are first-line pharmacotherapy for PTSD. Venlafaxine, the TCAs, and MAOIs may also be effective, but they have less favorable side effect profiles.

Sertraline and paroxetine are approved for acute treatment of PTSD, and sertraline is approved for long-term management of PTSD.

Antiadrenergics and atypical antipsychotics can be used as augmenting agents.

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The SSRIs are believed to be more effective for numbing symptoms than other drugs. About 60% of sertraline-treated patients showed improvement in arousal and avoidance/numbing symptoms. Similar numbers of patients have been shown to improve on paroxetine & fluvoxamine. Fluoxetine was effective in a placebo-controlled trial, and fluvoxamine & escitalopram were effective in an open trial.

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Sertraline & fluoxetine were effective in preventing relapse.

Amitriptyline and imipramine, and mitrazapine can be considered second line drugs.

Phenelzine is a third line drug for PTSD after SSRI have failed.

If there is no improvement in the acute stress response 3 to 4 weeks post trauma, SSRIs should be started in a low dose with slow titration upward toward antidepressant doses. Six to 12 weeks is an adequate duration of treatment to determine response.

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Responders to drug therapy should continue treatment for at least 12 months. When discontinued, drug therapy should be tapered slowly over a period of 1 month or more to reduce the likelihood of relapse.

Antiadrenergic drugs (prazosin) can be useful in some patients with PTSD, and antipsychotics (risperidone, quetiapine, and olanzapine), alfa1 adrenergic antagonists, antidepressants, mood stabilizers, anticonvulsants beta blockers & buspirone may be used as augmenting agents in partial responders.

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Patients should be seen weekly for the first month, then biweekly through the second month. During months 3 to 6, patients can be seen monthly, then every 1 to 2 months from months 6 to 12. Responders after 1 year of pharmacotherapy can be seen every 3 months. Patients should be monitored for symptom response, side effects, and treatment adherence.

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