Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report

Abstract Importance Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability). Objective Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression. Design Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. Setting Outpatient. Participants Adults with moderate–severe MDD with ≥ 4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (n = 214). Interventions Vagus nerve stimulation and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, and ketamine/esketamine) were characterized over the 12-month extension. Main Outcomes and Measures The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression–Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite measures with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori. Results Most participants with substantial benefit maintained their benefit (18-month median = 78.8%; 24-month median = 79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median = 83.1%; 24-month median = 81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median = 30.6%) and 24 (median = 37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatric modalities. Conclusions and Relevance Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year. Highlights

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Journal
The International Journal of Neuropsychopharmacology
Published
2025-12-20
DOI
https://doi.org/10.1093/ijnp/pyaf080
Citations
1
Primary Topic
Vagus Nerve Stimulation Research
Type
article
Field-Weighted Citation Impact
0.84

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article

Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report

Mark S. George, Matthew Macaluso, Ziad Nahas, Mark T. Bunker et al.
1 citations
The International Journal of Neuropsychopharmacology
Vagus Nerve Stimulation Research
0.84
article

Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report

Mark S. George, Matthew Macaluso, Ziad Nahas, Mark T. Bunker, Jeffrey I. Bennett, Harold A. Sackeïm, Rebecca M. Allen, Mary Stedman, Michael Banov, J.M. Way, Brian J. Mickey, Cristina Cusin, Lucian Manu, Ying-Chieh Lee, Walter Duffy, Patricio Riva‐Posse, Yvette I. Sheline, Gustavo Alva, John Zajecka, João Quevedo, Olivia Shy, Quyen Tran, Charles M. Gordon, Zorumski Cf, R. W. McIntyre, Christopher L Kriedt, Hunter Brown, Richard Hamish McAllister-Williams, Charles R Conway, David L Dunner, Scott T Aaronson, Augustus John Rush
article en
1 citations

Abstract

Abstract Importance Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability). Objective Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression. Design Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. Setting Outpatient. Participants Adults with moderate–severe MDD with ≥ 4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (n = 214). Interventions Vagus nerve stimulation and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, and ketamine/esketamine) were characterized over the 12-month extension. Main Outcomes and Measures The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression–Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite measures with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori. Results Most participants with substantial benefit maintained their benefit (18-month median = 78.8%; 24-month median = 79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median = 83.1%; 24-month median = 81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median = 30.6%) and 24 (median = 37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatric modalities. Conclusions and Relevance Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year. Highlights

The International Journal of NeuropsychopharmacologyVol. 29(1)
Rush University Medical Center (US), University of Minnesota (US), Emory University (US), Medical University of South Carolina (US), Huntsman (United States) (US), University of Toronto (CA), Southern Illinois University School of Medicine (US), Washington University in St. Louis (US), Cumbria Northumberland Tyne and Wear NHS Foundation Trust (GB), Huntsman Cancer Institute (US), Chattahoochee Technical College (US), University of Alabama at Birmingham (US), Psychiatric Medicine Associates (US), Stony Brook School (US), Massachusetts General Hospital (US), Clinical Research Institute (US), Sheppard Pratt Health System (US), Behavioral Health Systems (US), Alivation (United States) (US), Duke-NUS Medical School (SG), LivaNova (United Kingdom) (GB), Ralph H. Johnson VA Medical Center (US), Stedman Clinical Trials (US), ATP Clinical Research (United States) (US), Center for Anxiety and Depression (US), The University of Texas Health Science Center (US), Professional Beef Services (US), Perinatal Treatment Services (US), Stony Brook University (US), University of Newcastle Australia (AU), University of Pennsylvania (US), Newcastle University (GB)
Massachusetts General Hospital, Ohio State University, Emory University, Texas Tech University, University of Missouri, University of Minnesota, Carilion Clinic, Rush University, University of South Carolina, Augusta University, LivaNova, Stony Brook University, University of California, San Diego
Openalex Percentile: Top 19%
Vagus Nerve Stimulation Research
0.84
DOIOpen Access PDFOpenAlex
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