Part 1: First-Line Treatments
See part 2 of this special report here.

There’s a reason treatment-resistant anxiety is common in practice. Our first-line medications are not very effective for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) have only a small to moderate effect size in panic disorder (0.3–0.5). Cognitive behavioral therapy (CBT) performs a little better, but access to quality psychotherapy is a limitation.

Anxiety disorders are not interchangeable. Certain agents work in some disorders but not in others. In this issue, we’ll look at pharmacologic options for generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder (SAD), starting with the first-line options.

First steps

The anxiety disorders may diverge when it comes to second-line options, but they walk the same path of CBT and an SSRI or serotonin and norepinephrine reuptake inhibitor (SNRI) as first-line treatments. Dosing is similar among the three anxiety disorders and tends toward the higher side for these medications. The various SSRIs and SNRIs have comparable benefits, so how do we choose among them? If FDA approval is the goal, only paroxetine (20–60 mg/day) and venlafaxine (75–225 mg/day) check all the boxes. These are approved in all three disorders, but they carry a higher risk of withdrawal problems than the other serotonergic antidepressants. Paroxetine also has a higher risk of sexual and anticholinergic side effects and teratogenicity than other SSRIs, and venlafaxine carries a unique risk of ­hypertension.

Escitalopram (10–20 mg/day) and sertraline (50–200 mg/day) offer reasonable alternatives. Although not approved in all three disorders, they are supported by large controlled trials in all three (escitalopram is approved in GAD and sertraline in panic disorder and SAD). Escitalopram stands out for its lack of drug interactions and sertraline for its superior safety profile in heart disease. Fluoxetine (20–60 mg/day) is only approved in panic disorder, and citalopram (20–60 mg/day) and fluvoxamine (50–300 mg/day) have a few controlled trials but no FDA approvals in the three anxiety disorders.

Children and adolescents warrant a different initial approach, at least in GAD. Duloxetine is the only antidepressant with FDA approval in pediatric anxiety disorders, specifically in GAD for ages 7 and up (60–120 mg/day for all ages).* However, this SNRI does not have approval or controlled trials in other anxiety disorders, regardless of age.

What doesn’t work

In this issue, we’ll recommend off-label antidepressants when controlled trials support their use, but the ones that failed that test are just as important to know. Most notable is vortioxetine, which failed in several large, industry-sponsored trials of GAD. Small trials also suggest a lack of efficacy for bupropion, mirtazapine, nefazodone, and trazodone, particularly in SAD and panic disorder. Vilazodone has a small positive trial in SAD, but is otherwise untested in anxiety disorders (Pae CU et al, J Psychiatr Res 2015;64:88–98; Charney DS et al, J Clin Psychiatry 1986;47(12):580–586).

Anxiety is a nonspecific symptom, and when we endorse or dismiss a medication in this issue, we are speaking only of its effects in specific anxiety disorders rather than any global anxiolytic properties. Many of the medications that failed in anxiety disorders—particularly bupropion, mirtazapine, and vortioxetine—have good evidence to reduce anxiety when it occurs as part of major depression. 

See part 2 of this special report here.

*Erratum: Since this article went to print, escitalopram has been FDA approved for GAD.