Pharmaceutical Management of anxiety disorders

Pharmaceutical Management of anxiety disorders

In anxiety disorders the most prominent features are anxiety and avoidance which are irrational or impair functioning.

In anxiety disorders the most prominent features are anxiety and avoidance which are irrational or impair functioning.

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.

Chronic noradrenergic overactivity downregulates α2-adrenoreceptors in patients with generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Patients with social anxiety disorder (SAD) appear to have a hyperresponsive adrenocortical response to psychological stress.

γ-Aminobutyric acid (GABA) receptor model.

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). Many antianxiety drugs target the GABAA receptor. Benzodiazepines enhance the inhibitory effects of GABA, which regulates or inhibits serotonin (5-hydroxytroptamine; 5-HT), norepinephrine, and dopamine activity.

Anxiety symptoms may be linked to underactivity of GABA systems or downregulated central benzodiazepine receptors. In patients with GAD, benzodiazepine binding in the left temporal lobe is reduced. Abnormal sensitivity to antagonism of the benzodiazepine-binding site and decreased binding occurs in panic disorder. In generalized SAD there may be abnormal central GABAB receptor function. Abnormalities of GABA inhibition may lead to increased response to stress in PTSD.

5-HT model.

GAD symptoms may reflect excessive 5-HT transmission or overactivity of the stimulatory 5-HT pathways. Patients with SAD have greater prolactin response to buspirone challenge, indicating an enhanced central serotonergic response. The role of 5-HT in panic disorder is unclear, but it may be involved with development of anticipatory anxiety. 5-HT and dopamine systems may also be involved in the pathophysiology of generalized SAD.

Patients with PTSD hypersecrete corticotropin-releasing factor, but have subnormal levels of cortisol at the time of trauma and chronically. Dysregulation of the hypothalamic- pituitary-adrenal axis may be a risk factor for eventual development of PTSD.

Neuroimaging studies support the role of the amygdala, anterior cingulate cortex, and insula in the pathophysiology of anxiety. In GAD, there is an abnormal increase in the brain’s fear circuitry and increased activity in the prefrontal cortex. Patients with panic disorder have abnormalities of midbrain structures. Patients with SAD have greater activity in the amygdala and insula. In PTSD, the amygdala plays a role in the persistence of traumatic memory.

Management of anxiety disorders

Generalized anxiety disorder

The goals are to reduce severity, duration, and frequency of symptoms and improve functioning. The long-term goal is minimal or no anxiety symptoms, no functional impairment, prevention of recurrence, and improved quality of life.


Non-pharmacologic modalities include psychotherapy, short-term counseling, stress management, cognitive therapy, meditation, supportive therapy, and exercise. Ideally, patients with GAD should have psychological therapy, alone or in combination with antianxiety drugs. Cognitive behavioral therapy (CBT), though not widely available, is the most effective psychological therapy. Patients should avoid caffeine, stimulants, excessive alcohol, and diet pills.

• Hydroxyzine, often used in primary care, 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 to discontinue. Quetiapine extended release, 150 mg/day was superior to placebo and as effective as paroxetine 20 mg/day and escitalopram 10 mg/day, but with earlier onset of action.

The Food and Drug Administration (FDA) has established a link between antidepressant use and suicidality (suicidal thinking and behaviors) in children, adolescents, and young adults up to 24 years old. All antidepressants carry a black box warning advising caution in using antidepressants in this population, and the FDA also recommends specific monitoring parameters (consult the FDA-approved labeling or the FDA website).


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

• Selective serotonin reuptake inhibitors (SSRIs), extended-release venlafaxine, and duloxetine are effective in acute therapy (response rates of 60%–68%).

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

Benzodiazepine Therapy

The benzodiazepines are the most effective and frequently prescribed drugs for the treatment of acute anxiety. About 65% to 75% of patients with GAD have a marked to moderate response, and most of the improvement occurs in the first 2 weeks of therapy. They are more effective for somatic and autonomic symptoms of GAD, whereas antidepressants are more effective for the psychic symptoms (e.g., apprehension and worry).

Theoretically, benzodiazepines ameliorate anxiety through potentiation of GABA activity, but other neurotransmitters may also be involved. The dose must be individualized. The elderly are more sensitive to benzodiazepines and may experience falls when taking them.

The most common side effect of benzodiazepines is CNS depression. Tolerance usually develops to this effect. Other side effects are disorientation, psychomotor impairment, confusion, aggression, excitement, and anterograde amnesia.

Panic disorders

The goals are complete resolution of panic attacks, marked reduction in anticipatory anxiety, elimination of phobic avoidance, and resumption of normal activities. SSRIs are first-line agents 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. For patients who cannot or will not take medications, CBT alone is indicated. Educate patient to avoid caffeine, nicotine, alcohol, drugs of abuse, and stimulants.

If pharmacotherapy is used, antidepressants, especially the SSRIs, are preferred in elderly patients and youth. The benzodiazepines are second line in these patients because of potential problems with dis-inhibition. Usually patients are treated for 12 to 24 months before discontinuation is attempted over 4 to 6 months. Many patients require long-term therapy. Single weekly doses of fluoxetine have been used for maintenance.


Stimulatory side effects (eg, anxiety, insomnia, jitteriness) can occur in TCA- and SSRI-treated patients. This may hinder compliance and dose escalation. Low initial doses and gradual dose titration may eliminate these effects

Imipramine blocks panic attacks within 4 weeks in 75% of patients, but reducing anticipatory anxiety and phobic avoidance requires 8 to 12 weeks. 25% of panic disorder patients discontinue TCAs because of side effects. SSRIs eliminate panic attacks in 60% to 80% of patients within about 4 weeks, but some patients require 8 to 12 weeks. Approximately 54% to 60% of patients became panic-free on extended-release venlafaxine, 75 mg or 150 mg.


Benzodiazepines are second-line agents for panic disorder except when rapid response is essential. Avoid benzodiazepine monotherapy in patients with panic disorder who are depressed or have a history of depression. Avoid benzodiazepines in patients with a history of alcohol or drug abuse. They are often used concomitantly with antidepressants in the first 4 to 6 weeks to achieve a more rapid antipanic response.

Relapse rates of 50% or higher are common despite slow drug tapering. Alprazolam and clonazepam are the most frequently used benzodiazepines. Therapeutic response typically occurs within 1 to 2 weeks. With alprazolam, there may be breakthrough symptoms between doses. The use of extended-release alprazolam or clonazepam avoids this problem.

Social anxiety

The goals are to reduce the physiologic symptoms and phobic avoidance, increase participation in desired social activities, and improve quality of life. Patients with SAD often respond more slowly and less completely than patients with other anxiety disorders. After improvement, at least 1 year of maintenance treatment is recommended. Longterm treatment may be needed for patients with unresolved symptoms, comorbidity, an early onset of disease, or a prior history of relapse.

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.

CBT and social skills training are effective in children with SAD. SSRIs and serotonin norepinephrine reuptake inhibitors are effective in children 6 to 17 years of age. Individuals up to 24 years of age should be closely monitored for increased risk of suicide. Paroxetine, sertraline, extended-release fluvoxamine, and extended-release venlafaxine 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. Mixed results have been reported for fluoxetine. 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 doses of antidepressants. The dose should be tapered slowly (monthly) during discontinuation to decrease the risk of relapse. Efficacy with extended-release venlafaxine is well established.

Reserve benzodiazepines 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 benzodiazepine for treatment of generalized SAD. It should be tapered not faster than 0.25 mg every 2 weeks. Gabapentin was effective for SAD, with an onset of effect of 2 to 4 weeks. Pregabalin was superior to placebo at a dose of 600 mg/day.

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 before the performance to be sure adverse effects will not be problematic.

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

Monitor patients with SAD for symptom response, adverse effects, overall functionality, and quality of life. Evaluate patients weekly during dosage titration and monthly once stabilized. Ask patients to keep a diary to record symptoms and their severity and side effects. 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.


Post-traumatic stress disorder

The goals are to decrease core symptoms, disability, and comorbidity and improve quality of life. Immediately after the trauma, patients should receive treatment individualized to their presenting symptoms (eg, nonbenzodiazepine hypnotic or short courses of CBT). Brief courses of CBT in close proximity to the trauma can help prevent PTSD.

If symptoms persist for 3 to 4 weeks, and there is social or occupational impairment, patients should receive pharmacotherapy or psychotherapy, or both.

Psychotherapies for PTSD include stress management, eye movement desensitization and reprocessing (EMDP), and psychoeducation. Trauma-focused CBT (TFCBT) and EMDP are more effective than stress management or group therapy to reduce PTSD symptoms.

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

Antiadrenergics and atypical antipsychotics can be used as augmenting agents.

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.

Mirtazapine was effective in doses up to 45 mg/day and is a second-line agent. Amitriptyline and imipramine, are also second-line drugs. Phenelzine is a third line drug.

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

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

Prazosin, in daily doses of 1 to 4 mg, can be useful in some patients with PTSD.

Risperidone, quetiapine, α1-adrenergic antagonists, antidepressants, mood stabilizers, and anticonvulsants may be used as augmenting agents in partial responders.

See patients frequently for the first 3 months, then monthly for 3 months. In months 6 to 12, patients can be seen every 2 months. Monitor for symptom response, suicidal ideation, disability, side effects, and treatment adherence.



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