Vagus nerve stimulation (VNS™) for treatment-resistant depression: Efficacy, side effects, and predictors of outcome

Harold A. Sackeim, A. John Rush, Mark S. George, Lauren B. Marangell, Mustafa M. Husain, Ziad Nahas, Christopher R. Johnson, Stuart Seidman, Cole Giller, Stephen Haines, Richard K. Simpson, Robert R. Goodman

Research output: Contribution to journalArticlepeer-review

467 Scopus citations


This open pilot study of vagus nerve stimulation (VNS™) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD28 measure, 34.0% for the Montgomery-Äsberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p = .0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.

Original languageEnglish (US)
Pages (from-to)713-728
Number of pages16
Issue number5
StatePublished - 2001

Bibliographical note

Funding Information:
This study was supported in part by a grant from Cyberonics, Inc. We thank Burke T. Barrett and James M. Russell, M.D. for logistical support in preparing this manuscript.


  • Bipolar disorder
  • Clinical trial
  • Efficacy
  • Major depressive disorder
  • Side effects
  • Treatment-resistant depression
  • Vagus nerve stimulation


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