Applied Evidence

Treating anxiety without SSRIs

J Fam Pract. 2010 March;59(3):148-154

Author(s):

Are SSRI side effects a problem for your patient with generalized anxiety disorder? Here are some options to consider—and others to avoid.

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References

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12. Montgomery SA, Mahe H, Haudiquet V, et al. Effectiveness of venlafaxine, extended release formulation, in the short-term and long-term treatment of generalized anxiety disorder: results of a survival analysis. J Clin Psychopharmacol. 2002;22:561-567.

13. Meoni P, Hackett D, Lader M. Pooled analysis of venlafaxine XR efficacy on somatic and psychic symptoms of anxiety in patients with generalized anxiety disorder. Depress Anxiety. 2004;19:127-132.

14. Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial. JAMA. 2000;283:3082-3088.

15. Rynn M, Russell J, Erickson J, et al. Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety. 2008;25:182-189.

16. Kelsey JE. Efficacy, safety, and tolerability of venlafaxine XR in generalized anxiety disorder. Depress Anxiety. 2000;12 (suppl 1):S81-S84.

17. Kim TS, Pae CU, Yoon SJ, et al. Comparison of venlafaxine extended release versus paroxetine for treatment of patients with generalized anxiety disorder. Psychiatry Clin Neurosci. 2006;60:347-351.

18. Stahl SM. The ups and downs of novel antiemetic drugs, part 2: an illustration. J Clin Psychiatry. 2003;64:626-627.

19. Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J Clin Psychopharmacol. 2007;27:263-272.

20. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry. 2005;62:1022-1030.

21. Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol. 2003;2:240-249.

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

23. Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67:771-782.

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25. Davidson JR. First-line pharmacotherapy approaches for generalized anxiety disorder. J Clin Psychiatry. 2009;70(suppl 2):S25-S31.

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PRACTICE RECOMMENDATIONS

• Prescribe selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or selected anticonvulsants as first-line treatment for generalized anxiety disorder (GAD). A

• Avoid the use of benzodiazepines for long-term treatment of GAD. C

• Do not recommend valerian, kava extract, or St. John’s wort for the treatment of GAD; tell patients there is insufficient evidence of their efficacy. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

CASE 1 Brad S, a 39-year-old lawyer, is in your office for a follow-up visit. A month ago, you diagnosed him with generalized anxiety disorder and prescribed paroxetine. Brad reports that the medication worked “like a miracle,” rapidly resolving his constant worry and rumination. Unfortunately, though, he is experiencing a bothersome side effect—sexual dysfunction. He’s having difficulty achieving ejaculation during intercourse and wants to know if you can give him “something else that works just as well.” What would you recommend?

In any given year, about 6.8 million Americans—roughly 3.1% of people ages 18 and older—suffer from generalized anxiety disorder (GAD), according to the most recent national survey of psychiatric illness.^1,2 GAD is associated with overuse of medical services. In addition, patients with GAD frequently present with somatic illness, typically in primary care settings.^3-5 Women are twice as likely as men to be affected,⁶ and the onset of GAD more commonly occurs at or around midlife, rather than at earlier ages.⁴

Identifying and treating GAD promptly is a high priority, as it exacts a high burden of suffering. Physical and mental comorbidities are extremely common (TABLE). In fact, 66% of those with GAD have at least 1 additional psychiatric condition—most frequently, major depression.⁷

Further evidence of the toll GAD takes comes from the National Comorbidity Survey, a congressionally mandated study of more than 8000 US residents conducted in 1994. Among the respondents, 82% of those who had ever been diagnosed with GAD said they had sought professional help for the disorder, taken medication for it, or found that it interfered with their life or activities “a lot.” ⁷

Patients with GAD, like Brad, often start their search for help in primary care. And GAD can usually be treated successfully in such a setting.⁵ Thus, it is crucial for family physicians to not only be on the lookout for signs and symptoms of GAD (See “Is it GAD?”), but to familiarize themselves with the most effective pharmacological treatments.

FAST TRACK

The combination of fast onset of action, high efficacy, and lack of sexual side effects makes pregabalin an attractive drug for the treatment of generalized anxiety disorder.

While paroxetine, like other selective serotonin reuptake inhibitors (SSRIs), is well established as a safe and effective treatment for GAD,^8,9 1 or more of the most common side effects are often bothersome to patients. These include nausea, reported by 22% of patients; headache, reported by 12% of patients, and abnormal ejaculation/sexual dysfunction, reported by 11% of patients in a study of longterm use of paroxetine for GAD.¹⁰ This review describes the other options you may want to consider—and the ones you’ll want to avoid.

TABLE
GAD: Common comorbidities^7,44

Psychiatric	Hazard ratio	95% CI
Agoraphobia	19.2	9.1-40.8
Dysthymia	24.8	12.4-49.5
Major depression	13.9	7.9-24.2
Mania	19.6	7.24-53.27
Panic disorder	26.1	9.8-68.2
Substance abuse	1.99	0.68-11.41
Medical	Hazard ratio	95% CI
Atherosclerosis	1.99	0.93-4.13
Cerebrovascular disease	2.95	1.09-3.65
GI	1.40	1.13-1.73
Hypertension	1.33	1.05-1.66
Ischemic heart disease	1.50	1.10-2.04
Respiratory disease	1.28	1.08-1.47
CI, confidence interval; GAD, generalized anxiety disorder; GI, gastrointestinal.

Options are numerous, but which is best for your patient?

Many other drug classes and medications are used to treat GAD: tricyclic antidepressants, atypical antipsychotics, serotoninnorepinephrine reuptake inhibitors (SNRIs), anticonvulsants, benzodiazepines, and bupropion, among them. But a number of these options present problems of their own.

Tricyclics, for example, have demonstrated efficacy in treating GAD,¹¹ but are associated with sedation and anticholinergic side effects and are typically not as well tolerated as some other choices. Atypical antipsychotics also have troublesome side effects—primarily, somnolence and weight gain. In addition, atypical antipsychotics require monitoring for rare but life-threatening adverse reactions, such as agranulocytosis, which limits their practicality in a primary care setting.

Benzodiazepines, while rapidly alleviating feelings of anxiety, have significant withdrawal effects after long-term use. However, they are often used successfully as a short-term treatment for GAD. For that reason, we will include benzodiazepines—along with SNRIs, anticonvulsants, and bupropion—in our discussion of SSRI alternatives for GAD.

SNRIs have high efficacy
Of the 3 SNRIs on the market—desvenlafaxine, duloxetine, and venlafaxine—the latter 2 are approved for the treatment of GAD. Venlafaxine, in particular, has shown great efficacy as both a short- and long-term treatment.^12-14

A meta-analysis by Meoni et al demonstrated that venlafaxine ER (extended release) provided significantly higher response rates than placebo for the relief of both the psychological and somatic symptoms of GAD.¹³ By week 24 of treatment, the rates of improvement in the treatment group were 66% for psychological symptoms and 67% for somatic symptoms, vs 35% and 47%, respectively, for those in the placebo group. A randomized controlled trial (RCT) by Montgomery et al also found venlafaxine to be well tolerated, with no significant difference in rates of discontinuation due to adverse effects between the SNRI and placebo.¹² (In another study, duloxetine was found to be an effective treatment for GAD, but had a significantly higher dropout rate than placebo.¹⁵)