Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are first-line pharmacotherapy for most patients with generalized anxiety disorder and social anxiety disorder, but a substantial number of patients need more.
How many is unclear. "Treatment resistance in anxiety is not as well defined as in depression. There are [fewer data]," said Dr. Mary Elizabeth Salcedo, medical director of an anxiety treatment center in Washington. "But it appears as common and as difficult [to resolve]."
In Dr. Salcedo's experience, at least 30% of patients are left with "a significant amount of troubling anxiety" after trials of several first-line agents.
For generalized anxiety disorder (GAD), Dr. Olga Brawman-Mintzer, director of the anxiety disorders program at the Medical University of South Carolina in Charleston, put the proportion at 40%. If remission is the goal, considerably more will require treatment beyond the serotonin reuptake inhibitor, she said.
Psychiatric comorbidity is a "frequently overlooked" factor in poor response, she said, noting that "major depression is highly comorbid with GAD; the lifetime prevalence is approximately 80%. Other anxiety disorders are frequent as well."
Untreated attention-deficit/hyperactivity disorder and bipolar disorder are other possibilities. "In a patient with mild cyclothymic disorder, anxiety could respond to treatment with a mood stabilizer," Dr. Salcedo said.
Substance abuse also predicts poor response, and Dr. Brawman-Mintzer pointed out that even rather modest alcohol use can undermine medication compliance in these patients. Poor adherence also can take the form of underdosing: "These patients tend to worry about potential adverse effects of psychotropic medications, [so they take] lower-than-prescribed doses," she said.
When patients have a partial response to a first-line drug, augmentation is the usual next step. "At this point, there's not much empirical data. It comes down to the clinician's clinical preference and experience, and--for some patients--to cost," said Dr. Michael Van Ameringen, who is codirector of the anxiety disorders clinic at McMaster University Medical Centre in Hamilton, Ont.
"When thinking about switching or combining things, it is best to look at agents that have a different mechanism of action," he suggested.
The most common candidates to combine with antidepressant medications include the atypical antipsychotics; benzodiazepines or buspirone; and anticonvulsants.
"I use atypicals a lot," Dr. Salcedo said. "They provide an acute, all-day calming effect and help with sleep." She is particularly likely to opt for an atypical antipsychotic when mood symptoms are prominent, or when symptoms are especially distressing.
Dr. Salcedo shies away from olanzapine (Zyprexa) out of concern for weight gain and metabolic effects. Because akathisia is particularly to be avoided in an anxious patient, she often chooses quetiapine (Seroquel) over risperidone (Risperdal).
Dr. Brawman-Mintzer noted that there is some evidence, for the most part in small trials, that low-dose atypical antipsychotics may be effective as augmenting agents in treatment-resistant GAD patients, and said that she has had some good results with very low doses, usually given at night; this might mean 0.5-1 mg of risperidone or 50-100 mg of quetiapine. …