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PHARMACOLOGIC TREATMENT OF ANXIETY DISORDERS

Anxiety and anxiety disorders are common clinical problems. The twelve-month community prevalence rates for the major anxiety disorders range from 0.7% for obsessive-compulsive disorder to 2.3% for panic disorder.¹ Untreated anxiety may be a significant source of distress and impairment. Anxiety disorder may be effectively managed by pharmacologic treatment, psychotherapy, or a combination of medication and therapy. The initial selection of specific pharmacologic treatment is often based on the anticipated duration of the anxiety. Acute (and time-limited) anxiety can often be managed with short-term benzodiazepine therapy. Chronic anxiety is often better managed with medications in the antidepressant class.

Treatment should be selected after a careful review of specific drug indications, adverse effects, drug-drug interactions, cost, and clinician experience. Patients should be informed of the risks and benefits of suitable pharmacologic agents. With all antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, the clinician should review the potential for idiosyncratic increase in anxiety and agitation. Additionally, patients should be aware of the potential for the rare emergence of suicidal ideation.² Since SSRIs and benzodiazepines can produce significant withdrawal syndromes, patients should be instructed about the need to taper medications under a physician’s care, should they decide to discontinue their medications.³

Role of benzodiazepines

Acute stress-related anxiety can result in the development of adjustment disorder with anxious mood. Physicians may encounter patients with high anxiety related to medical illness. For example, an excessively anxious patient awaiting the result of biopsy may meet criteria for adjustment disorder. The diagnosis of adjustment disorder requires that the patient's anxiety level exceed that expected for the stressor. Since adjustment disorder with anxious mood often improves with time, a limited duration of pharmacologic treatment is indicated. For milder acute anxiety, a process of observation may be appropriate to monitor an expected resolution of symptoms over time.

Benzodiazepines produce a rapid-onset anxiolytic effect and may be the agents of choice for adjustment disorder with anxiety with an anticipated duration of treatment of less than 6 weeks. Many benzodiazepines also have intravenous formulations that can be used in the emergency room or preoperatively. However, clinicians should review the risk for benzodiazepine misuse before prescribing. This risk is increased for patients with a personal history of alcohol abuse or illicit substance dependence. Other risk factors for misuse include a family history of alcohol abuse or family history of substance dependence. Finally, benzodiazepine therapy should be avoided in patients with antisocial personality disorder.

Since benzodiazepines have limited effect on depression, these agents should not be used as monotherapy for patients with anxiety in the context of significant depression.

When using benzodiazepines to treat acute anxiety, dosage titration is required to limit risk of adverse effects. Higher daily doses of benzodiazepines may raise risk of falls and other types of accidents. The ability to form memories can be impaired during the time benzodiazepines are in the blood. Patients should not drink alcohol while taking benzodiazepines.

Role of selective serotonin reuptake inhibitors

Chronic anxiety should produce a search for a specific anxiety disorder diagnosis. Generalized anxiety disorder, panic disorder, social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder are common causes of chronic anxiety. SSRIs appear to be effective across many of the specific anxiety disorders. The SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. Some of these agents have specific indications approved by the US Food and Drug Administration (FDA) for individual anxiety disorder diagnostic categories. However, most head-to-head comparisons between agents in the SSRI class find similar response rates for individual anxiety disorder categories.⁴

Although the SSRIs appear to have equal efficacies for anxiety disorders, a trial with a second SSRI may be indicated after failure with the first SSRI. Some individual patients appear to respond better to one SSRI than to another. The only valid way to determine which SSRI will produce a response in a particular patient is to perform clinical trials.

Role of other antidepressant compounds

Tricyclic antidepressants (TCAs) have been effective for the treatment of many anxiety disorders. Imipramine has been studied and found to be effective in a variety of anxiety states. Clomipramine has an FDA indication for the treatment of obsessive-compulsive disorder. Although TCAs have clinical effectiveness for many anxiety disorders, their limited tolerability and toxicity in overdose make them second-line agents for many patients.

Newer antidepressants are available with good tolerability and serve as reasonable alternatives to TCAs and SSRIs. Venlafaxine is a dual-action reuptake inhibitor that blocks the reuptake of both serotonin and norepinephrine. It has been approved by the FDA for the treatment of generalized anxiety disorder, social phobia, and panic disorder.⁵ Duloxetine is also a dual-action reuptake inhibitor; it has not yet received extensive study in the treatment of anxiety disorders.

Monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine appear to have significant anti-anxiety properties. These agents may be considered for patients with social phobia or posttraumatic stress disorder. MAOIs can produce hypertensive crisis in interactions with some drugs and foods with high tyramine content. This interaction limits their usefulness except in patients whose symptoms are refractory to other treatment.

Role of other agents

A host of other pharmacologic agents from other drug classes may be helpful in the management of anxiety. Buspirone is an agent that may prove helpful in generalized anxiety disorder. Pregabalin and gabapentin are anti-epileptic drugs with structures similar to gamma-aminobutyric acid (GABA). These agents have limited abuse potential and may have a role in the treatment of anxiety disorders.⁶ Their role in anxiety management is likely to emerge with further clinical trials.

Some clinicians have found anticholinergic agents such as diphenhydramine or hydroxyzine as helpful in managing anxiety. Use of these drugs should be limited in geriatric populations because of the risk of memory impairment and anticholinergic delirium.

The agents in the atypical antipsychotic class, including risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole, may be considered for patients with treatment-resistant anxiety disorders.⁷ Atypical antipsychotic augmentation of an SSRI in posttraumatic stress disorder and obsessive-compulsive disorder may provide incremental clinical improvement.

Treatment guidelines

Guidelines for treatment of anxiety disorders provide additional details about pharmacologic treatment. Available guidelines cover all of the major anxiety disorder categories.8 Guidelines are also available for some of the individual anxiety disorder categories and for management of anxiety in primary care populations.^9,10

References

1. Wittchen HU, Jacobi F. Size and burden of mental disorder in Europe: a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005;15:357-76.

2. Tamam L, Ozpoyraz N. Selective serotonin re-uptake inhibitor discontinuation syndrome: a review. Adv Ther 2002;19:17-26.

3. Aursnes I, Tvete IF, Gaasemyr J, Natvig B. Suicide attempts in clinical trials with paroxetine randomized against placebo. BMC Med 2005;3:14.

4. Ball SG, Kuhn A, Wall D, et al. Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind, prospective comparisons between paroxetine and sertraline. J Clin Psychiatry 2005;66:94-9.

5. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine in social anxiety disorder. Arch Gen Psychiatry 2005;62:190-8.

6. Van Ameringen M, Mancini C, Pipe B, Bennett M. Antiepileptic drugs in the treatment of anxiety disorders: role in therapy. Drugs 2004;64:2199-220.

7. Simon NM, Hoge EA, Fischmann D, et al. An open-label trial of risperidone augmentation for refractory anxiety disorders. J Clin Psychiatry 2006; 67:381-5.

8. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacologic treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005;19:67-96.

9. Ursano RJ, Bell C, Eth S, et al. Practice guideline for the treatment of patients with acute stress disorder and post-traumatic stress disorder. Am J Psychiatry 2004;161(11 Suppl):3-31.

10. McIntosh A, Cohen A, Turnbull N, et al: Clinical guidelines for the management of anxiety. Management of anxiety (panic disorder, with or without agoraphobia, and generalized anxiety disorder) in adults in primary, secondary and community care. London: National Institute of Clinical Excellence (NICE); 2004.