A prospective, open-label study reported in the American Journal of Psychiatry found that adjunctive treatment with vagus nerve stimulation (VNS) was more effective than treatment as usual (TAU) for treatment-resistant depression.1

Treatment-resistant depression is defined as major depression that does not respond to at least 2 complete trials of 2 different classes of antidepressant therapy. Previous findings reveal that “32% to 41% of patients with treatment-resistant depression fail to remit after four trials of antidepressants, resulting in a large population of symptomatically and functionally impaired individuals,” wrote the investigators in the current study.2,3

VNS is an FDA-approved treatment that has been found to be effective as adjunctive therapy in this patient population, and it is recommended by the American Psychiatric Association in patients who demonstrate non-responsiveness to at least 4 different courses of treatment.4,5 As part of the US Food and Drug Administration (FDA)-approval process, researchers from several US universities conducted a 5-year non-randomized observational study that included 795 adult patients with treatment-resistant depression at 61 sites across the United States.

The study compared outcomes in 2 cohorts of patients who both received treatment as usual (TAU), and 1 group who received VNS (n=494). In the VNS group, the device was implanted before the baseline visit, and subsequent visits were scheduled for all patients every 3 months for the first year and every 6 months thereafter for the remainder of the 5-year study period. At each follow-up visit, various clinical data were collected, including scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), which served as the primary outcome.

The following significant results were observed:

  • Higher 5-year cumulative response rate in the VNS group vs the TAU group (67.6% [95% CI, 63.4-71.7] vs 40.9% [95% CI, 35.4-47.1]; P <.001)
  • Higher rate of first-time remitters in the VNS group vs the TAU group (43.3% [95% CI, 38.9-47.7] vs 25.7% [95% CI, 20.7-31.1]; P <.001)
  • In patients who had previously responded to electroconvulsive therapy (ECT), a higher cumulative response rate in the VNS group vs the TAU group (71.3% [95% CI, 64.3-77.4] vs 56.9% [95% CI, 44.8-68.2], P =.006)
  • In patients who had not previously responded to ECT, a higher cumulative response in the VNS group vs the TAU group (59.6% [95% CI, 50.2-68.4] vs 34.1% [95% CI, 21.8-48.9]; P <.001)
  • Lower all-cause mortality in the VNS group vs the TAU group (3.53 per 1000 person-years [95% CI, 1.41-7.27] vs 8.63 per 1000 person-years [95% CI, 3.72-17.01]
  • Lower rate of completed suicides in the VNS group vs the TAU group (1.01 per 1,000 person-years [95% CI, 0.11-3.64] vs 2.20 per 1000 person-years [95% CI, 0.24-7.79]

Taken together, these findings demonstrate the effectiveness of VNS as an adjunctive therapy for treatment-resistant depression. “As there is a lack of evidence-based biological treatment options for treatment-resistant depression (other than ECT), the results from this registry provide encouragement to pursue aggressive neurostimulation interventions,” wrote the investigators.


  1. Aaronson ST, Sears P, Ruvuna F, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality [published online March 31, 2017]. Am J Psychiatry. doi:10.1176/appi.ajp.2017.16010034
  2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. doi:10.1176/ajp.2006.163.11.1905
  3. Agency for Healthcare Research and Quality (AHRQ): Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults (Comparative Effectiveness Review Number 33). Rockville, MD, AHRQ, 2011. https://effectivehealthcare.ahrq.gov/ehc/ products/76/792/TRD_CER33_20111110.pdf. Accessed June 2, 2017.
  4. Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58(5): doi:10.1016/j.biopsych.2005.05.024
  5. American Psychiatric Association: Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. Washington, DC, American Psychiatric Association, 2010.