Optimizing Outcomes for Patients with Treatment-Refractory Anxiety Disorder

Treatment-refractory anxiety disorders are not uncommon but may be difficult to treat. During a presentation at the Neuroscience Education Institute Max! Virtual Meeting, Jeffrey R. Strawn, MD, associate professor in the Department of Pediatrics at the University of Cincinnati, discussed treatment options and strategies for treatment-refractory disease.

Not until the last year or so was there a consensus definition of treatment-resistant anxiety, he said. These are patients who have failed at least one first-line treatment with a selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI), have failed at least one psychotherapeutic treatment (e.g., cognitive behavioral therapy), and have persistent symptoms in the moderate range.

There are considerably high relapse rates in patients with treatment-resistant anxiety, he said, and risk of recurrence significantly increases over time. Unrecognized substance use, over-the-counter medications, situational and interpersonal context, and comorbidities can all co-occur with treatment-resistant anxiety and should be monitored. Medical factors could also contribute to treatment-resistant anxiety, including tachyarrhythmias, thyroid disease, concurrent medications, and concurrent marijuana use.

Dr. Strawn advised an algorithmic approach to diagnostic reevaluation. In a patient with significant anxiety-related symptoms and impairment function, identify the prominent symptom focus and comorbidities. For intermittent anxiety, identify the root of it. Difficult-to-control anxiety may be about multiple things and would be classified as generalized anxiety disorder (GAD). “As we begin to move to precision medicine, we know that these individual disorders predict differences in terms of long-term outcomes and adjunct treatments that may have benefit,” he said.

While SSRIs and SNRIs are treatment mainstays for anxiety disorders, multiple randomized, controlled trials support the efficacy of pregabalin and quetiapine, raising the possibility that these agents might be tried in patients who have failed first-line treatment.

Quetiapine is used off-label for anxiety. A study of quetiapine for GAD observed relatively early improvements, he said. Adverse events (AEs) associated with quetiapine include dry mouth, somnolence, fatigue, dizziness, and headache. Pregabalin uses a “unique” mechanism of action, he said. In long-term studies, maintained improvements and delayed relapse were observed compared with placebo. AEs observed include dizziness, somnolence, and “significant” weight gain. Pregabalin tends to have a rapid onset of action, and improvements appear to be maintained over time. Pregabalin should be tapered rather than discontinued abruptly, he noted.

SSRIs and SNRIs are first-line therapies that should be continued when patients respond. In the event that these therapies fail or the response is limited, “we have to look deeper,” said Dr. Strawn. With a partial response, think in terms of augmentation strategies, he advised, including buspirone, long-acting benzodiazepines, and pregabalin.

When there isn’t a response, a patient can switch to another SSRI or SNRI. “We can be savvy in terms of our psychopharmacology in choosing that second SSRI/SNRI,” he said, advising that physicians pick an SSRI/SNRI that is metabolized differently than the first. If patients respond to the second SSRI/SNRI, continue pharmacotherapy for 12 months rather than six months, according to Dr. Strawn. If patients do not respond to the second SSRI/SNRI, consider tricyclic antidepressants, quetiapine, or monoamine oxidase inhibitors (MAOIs). However, he cautioned that MAOIs are associated with weight gain, so he recommends referring patients to a dietician — which is often covered by insurance — to review their diet.

When prescribing for this patient population, Dr. Strawn also recommends requesting counseling from a pharmacist who can consider drug-drug interactions.

Presentation: Nothing to Worry About: Treatment Refractory Anxiety Disorders. Presented at the Neuroscience Education Institute Max! Virtual Meeting, Nov. 5-8, 2020.