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Harold A Sackeim,1 Maxine Dibué,2,3 Mark T Bunker,4 A John Rush5– 7 1Departments of Psychiatry and Radiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; 2Department of Neurosurgery, Heinrich Heine University, Düsseldorf, Germany; 3Medical Affairs Europe, LivaNova Deutschland GmbH, Munich, Germany; 4LivaNova USA PLC, Houston, TX, USA; 5Duke-NUS Medical School, Singapore; 6Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; 7Department of Psychiatry, Texas Tech University, Permian Basin, TX, USACorrespondence: Harold A SackeimDepartments of Psychiatry and Radiology, Vagelos College of Physicians and Surgeons, Columbia University, 2124 Moselem Springs Road, Fleetwood, PA 10522, USATel +1 917 273-5379Email has1@columbia.eduPurpose: The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population.Methods: A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described.Results: Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life.Limitations: Most comparisons of VNS+TAU and TAU were derived from observational, open label studies.Conclusion: The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.Keywords: vagus nerve stimulation, major depressive episode, difficult-to-treat depression, treatment-resistant depression, antidepressant, efficacy, regulatory process |
