Evidence-Based Reviews

Generalized anxiety disorder: Helping patients overcome worry

Current Psychiatry. 2012 May;11(5):40-44

References

1. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.

2. Andrews G, Hobbs MJ, Borkovec TD, et al. Generalized worry disorder: a review of DSM-IV generalized anxiety disorder and options for DSM-V. Depress Anxiety. 2010;27(2):134-147.

3. Turk CL, Mennin DS. Phenomenology of generalized anxiety disorder. Psychiatr Ann. 2011;41(2):72-78.

4. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627.

5. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on generalized anxiety disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2001;6(suppl 11):53-58.

6. Kessler RC, Keller MB, Wittchen HU. The epidemiology of generalized anxiety disorder. Psychiatr Clin North Am. 2001;24(1):19-39.

7. Kavan MG, Elsasser G, Barone EJ. Generalized anxiety disorder: practical assessment and management. Am Fam Physician. 2009;79(9):785-791.

8. Spitzer RL, Kroenke K, Williams JBW, et al. A brief measure for assessing generalized anxiety disorder. Arch Intern Med. 2006;166(10):1092-1097.

9. Newman MG, Borkovec TD. Cognitive-behavioral treatment of generalized anxiety disorder. Clin Psychol. 1995;48(4):5-7.

10. Leichsenring F, Salzer S, Jaeger U, et al. Short-term psychodynamic psychotherapy and cognitive-behavioral therapy in generalized anxiety disorder: a randomized, controlled trial. Am J Psychiatry. 2009;166(8):875-881.

11. Evans S, Ferrando S, Findler M, et al. Mindfulness-based cognitive therapy for generalized anxiety disorder. J Anxiety Disord. 2008;22(4):716-721.

12. Stein MB, Sherbourne CD, Craske MG, et al. Quality of care for primary care patients with anxiety disorders. Am J Psychiatry. 2004;161(12):2230-2237.

13. Fricchione G. Generalized anxiety disorder. N Engl J Med. 2004;351(7):675-682.

14. Rickels K, Downing R, Schweizer E, et al. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50(11):884-895.

15. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Cochrane Database Syst Rev. 2010;(12):CD006815.-

16. Gammans RE, Stringfellow JC, Hvizdos AJ, et al. Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms. A meta-analysis of eight randomized, controlled studies. Neuropsychobiology. 1992;25(4):193-201.

17. Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006;(3):CD006115.-

18. Sramek JJ, Tansman M, Suri A, et al. Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms. J Clin Psychiatry. 1996;57(7):287-291.

19. Rickels K, DeMartinis N, García-España F, et al. Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Am J Psychiatry. 2000;157(12):1973-1979.

20. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry. 1998;155(7):992-993.

21. Khan A, Joyce M, Atkinson S, et al. A randomized, double-blind study of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder. J Clin Psychopharmacol. 2011;31(4):418-428.

22. Mathew SJ, Amiel JM, Coplan JD, et al. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry. 2005;162(12):2379-2381.

23. Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003;160(3):533-540.

24. Coric V, Feldman HH, Oren DA, et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety. 2010;27(5):417-425.

25. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD003383.-

26. Zoberi K, Pollard CA. Treating anxiety without SSRIs. J Fam Pract. 2010;59(3):148-154.

Differential diagnosis

GAD typically has a chronic course with fluctuating symptom severity over the patient’s lifespan. Assess patients who present with anxiety for medical conditions that mimic GAD. These include:

endocrine (hyperthyroidism), metabolic (electrolyte abnormalities), respiratory (asthma), neurologic (seizure disorder), or cardiac (arrhythmia) conditions
nutritional deficiencies, especially of B vitamins and folate
ingestion of substances or medications that may cause anxiety, such as caffeine or amphetamines.

A thorough history, medication review, and physical examination—as well as routine tests such as metabolic panel, complete blood count, thyroid function tests, urine drug screen, and electrocardiography—will capture most of these potential etiologies. In addition to ruling out medical causes, also assess for comorbid psychiatric conditions before reaching a diagnosis.

Clinical Point

GAD typically has a chronic course with fluctuating symptom severity over the patient’s lifespan

Evidence-based treatments

The treatment armamentarium for GAD includes psychotherapy and pharmacotherapy; complementary and alternative medicine (CAM) modalities may be useful adjunctive treatments. Which approach to use is determined by clinical judgment and the patient’s symptom severity and preferences. Combination therapy consisting of psychotherapy and medication often is appropriate.

Psychotherapy. Cognitive-behavioral therapy (CBT) is the preferred form of psychotherapy for GAD because it results in sustained improvements for patients with anxiety.^5,9 Other modalities that may be effective include psychodynamic psychotherapy, mindfulness-based therapy, and interpersonal psychotherapy.^10,11

Pharmacotherapy. As few as one-quarter of patients with GAD receive medications at appropriate dose and duration.¹² Antidepressants are a first-line pharmacotherapy.⁵ Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors are highly effective for treating GAD.⁵ Paroxetine, escitalopram, duloxetine, and venlafaxine are FDA-approved for GAD, but other SSRIs also are used as primary treatment.⁵ Assuming the selected agent is tolerable and efficacious, a treatment course of 12 months is recommended.¹³

Clinical Point

Antidepressants are a first-line treatment for GAD; SSRIs and SNRIs are highly effective

Benzodiazepines promote binding of the neuroinhibitory transmitter γ-aminobutyric acid and enhance chloride ion influx, thus reducing anxiety. Benzodiazepines have been widely used because of their rapid onset of action and effectiveness in managing anxiety, but their role in long-term management of GAD is unclear because these medications increase the risk of addiction, cognitive dulling, memory impairment, psychomotor retardation, and respiratory depression when combined with other CNS depressants such as alcohol and opiates. Before prescribing a benzodiazepine, conduct a thorough risk-benefit analysis and obtain informed consent. Long-term benzodiazepine monotherapy is not recommended.^5,14

Hydroxyzine is an alternative to benzodiazepines.¹⁵ It works as an antihistamine and is FDA-approved for psychogenic neurosis, a Freudian distinction encompassing anxiety derived from psychological rather than physiological factors.

The azapirone buspirone is a nonaddictive, generally non-sedating 5-HT1A agonist. Although anecdotally some psychiatrists may report limited clinical utility, many analyses found azapirones, including buspirone, were effective for GAD,^16,17 particularly for patients with comorbid depression.¹⁸

Clinical Point

Cognitive-behavioral therapy results in sustained improvements for patients with anxiety

Tricyclic antidepressants are not a first-line choice because of their side effect profile and potential for drug-drug interactions. Nonetheless, some research suggests imipramine may be a reasonable option for GAD.^14,19

Although not FDA-approved for GAD, anticonvulsant and antipsychotic medications may be reasonable adjunctive agents for patients with refractory GAD. Studies have suggested gabapentin²⁰ and quetiapine²¹ as options.

Investigational treatments. Glutaminergic transmission is being investigated as a target for pharmacotherapy for GAD. In an 8-week, open-label trial, 12 of 15 GAD patients responded to the antiglutamatergic agent riluzole, 100 mg/d, and 8 patients achieved remission.²² In another study, pregabalin, which promotes calcium channel blockade, significantly reduced patients’ scores on the Hamilton Anxiety Rating Scale.²³ However, this medication is a schedule V controlled substance and little is known about its long-term effects. Researchers had proposed that inhibition of corticotropin-releasing factor (CRF) may help reduce anxiety, but in a double-blind, placebo-controlled trial, they found that the CRF antagonist pexacerfont was no more effective than placebo.²⁴

CAM treatments. A meta-analysis found that compared with placebo, kava extract (Piper methysticum) effectively reduced anxiety symptoms.²⁵ However, considering its risk for hepatotoxicity, kava is not a recommended treatment.²⁶ Although valerian, St. John’s wort, and passionflower have been used to manage GAD, there is insufficient evidence of their effectiveness and safety.²⁶ No strong evidence supports nutritional supplements such as ginger, amino acids, and omega-3 fatty acids (fish oils) as treatment for GAD. Although there’s limited research on resistance training, aromatherapy, yoga, meditation, or acupuncture for treating anxiety, consider these treatments if your patient finds them helpful, because generally they are not contraindicated.

Clinical Point

No strong evidence supports nutritional supplements such as ginger or omega-3 fatty acids for treating GAD