Treatment Resistance Beyond Primary Care

Patients who fail to respond sufficiently to at least two SSRIs, one SNRI, and CBT should be referred to a psychiatrist who is experienced in treatment-resistant anxiety. Second-line treatment may include diagnosing comorbidity, adding treatment for comorbidity, adding a tricyclic antidepressant with an SSRI, and trying atypical antipsychotics.

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“Atypical antipsychotics like pregabalin (Lyrica) or gabapentin (Neurontin) may be used for crisis management,” Salcedo says. “These drugs have some serious long-term side effects, so they need to be used with care. If bipolar disorder is suspected, adding lithium may help. The main thing to know is that most patients with anxiety disorders can be managed .”

Future Treatments for Anxiety

In his Molecular Psychiatry review, Bystritsky mentioned the possibility that nonpharmacologic treatments – like deep brain stimulation, vagus nerve stimulation, stereotactic neurosurgery, and transcranial magnetic stimulation (TMS) – may eventually play a role in treatment-resistant anxiety.

“Of these possibilities, TMS has shown the most promise. I think TMS is where the SSRIs were in the 1970s,” he says.

“There are still many parameters to fiddle with. We need to learn more about how the circuits work and interact,” Bystritsky continues. “But transcranial direct current is noninvasive, has no downside, and has a building body of supportive research. Even if it is partly a placebo effect, it can be used if it works. We will see what develops in the next 10 years.”

Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts.

This article was medically reviewed by Lindsey Marcellin, MD, MPH.


  1. Bystritsky A. Treatment-Resistant Anxiety Disorders. Molecular Psychiatry. 2006; 11:805-814.
  2. Interview with Alexander Bystritsky, MD, PhD, Director, Anxiety Disorders Program, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles.
  3. Interview with Mary Beth Salcedo, MD, Medical Director, Ross Center for Anxiety and Related Disorders, Washington, D.C.
  4. Copland JD and Reddy DP. Treatment-Resistant Anxiety Disorders: Neurotrophic PerspectivesPsychiatric Times. October 31, 2006.
  5. Learning Your ABCs.