Researchers followed patients with extremely persistent depression to see whether a surgically implanted nerve-stimulation device could produce lasting change. Over time, many participants showed continued gains in emotional stability and everyday functioning, with some improving only after prolonged treatment. Credit: Shutterstock
Research shows that vagus nerve stimulation can provide long-lasting benefits for patients who do not respond to conventional treatments
Around 20% of adults in the United States will experience major depression at some point in their lives. Many people feel better after trying a few treatments. But for as many as one in three patients, depression remains despite standard antidepressants or psychotherapy, a condition known as treatment-resistant depression. A new study suggests that an implanted device could offer meaningful, long-lasting relief for people with the most severe forms of this illness.
The research was led by a team at Washington University School of Medicine in St. Louis, which oversaw a large clinical trial conducted at multiple sites. The device works by stimulating the vagus nerve, and investigators found improvements in depressive symptoms, quality of life, and other outcomes such as function. For most participants who were already benefiting at one year, those gains continued for at least two years. On average, patients had tried 13 unsuccessful treatments before enrolling, including electroconvulsive therapy and transcranial magnetic stimulation, and had lived with depression for 29 years.
The results come from the ongoing RECOVER trial and were published in the International Journal of Neuropsychopharmacology.
“We believe the sample in this trial represents the sickest treatment-resistant depressed patient sample ever studied in a clinical trial,” said lead author Charles Conway, MD, a professor of psychiatry and director of the WashU Medicine Treatment Resistant Mood Disorders Center. “There is a dire need to find effective treatments for these patients, who often have no other options. With this kind of chronic, disabling illness, even a partial response to treatment is life-altering, and with vagus nerve stimulation we’re seeing that benefit is lasting.”
Getting better, staying better
The RECOVER study was created to test whether vagus nerve stimulation (VNS) can improve results when added to a patient’s existing care for treatment-resistant depression. In this approach, doctors implant a device beneath the skin of the chest. It delivers precisely timed electrical pulses to the left vagus nerve, which carries signals between the brain and many internal organs.
The device used in the study, the VNS Therapy System, is made by LivaNova USA, Inc., which also sponsored and funded the RECOVER trial. Researchers are collecting detailed information on changes in mood, daily functioning, and quality of life in people with markedly treatment-resistant depression. One aim is to provide data that the U.S. Centers for Medicare and Medicaid Services (CMS) can use when considering whether to cover the therapy. Cost is a major barrier for many patients right now. Because private insurers often follow CMS decisions, broader coverage could make the implant and surgery accessible to many more people.
Nearly 500 patients took part in the trial at 84 locations across the country. About three-quarters were so severely affected that they could not work. Every participant received an implanted VNS device, but during the first year, only half of the devices were activated to allow for a controlled comparison. Researchers tracked changes in depression severity, quality of life, and daily function.
A response was considered meaningful if symptoms dropped by at least 30% compared with baseline. A “substantial” response meant symptoms decreased by at least 50%.
Conway, the principal investigator of RECOVER, emphasized that even a 30% reduction can significantly change life for someone with severe depression. The condition can leave people “paralyzed by life,” unable to manage everyday tasks and facing a much higher risk of hospitalization or early death.
Sustained Benefits Over Two Years
Earlier reported outcomes from the blinded first year of the RECOVER trial demonstrated that people with activated devices spent significantly more time with improved depressive symptoms, quality of life, and daily function than did those with inactive devices, although the primary outcome measure (the Montgomery-Åsberg depression scale, which measures the severity of depressive episodes) did not significantly differ between the two groups.
In this updated analysis of the ongoing trial, Conway and his colleagues examined only the patients who received active treatment during the first year of the RECOVER trial to determine whether improvements seen at 12 months would be sustained through 24 months. The team also assessed whether patients who showed no benefit at 12 months of activation might improve after more time with VNS.
Of 214 patients receiving active treatment from the beginning of the trial, about 69%, or 147 people, had a meaningful response at 12 months in at least one metric. Among those patients who experienced a meaningful benefit at 12 months, more than 80% maintained or increased benefits at 24 months across all measures of depression, quality of life, and function. And among patients who had a substantial response at one year — defined as 50% or greater symptom reduction — 92% were typically still experiencing a benefit at the two-year mark, across all measures.
What’s more, nearly one-third of participants who had not responded after one year of treatment reported benefits at the end of the second year, suggesting the treatment might take more time to work in some people.
Late Responses and Remission
Among those who experienced benefits at one year, relapse rates were consistently low, especially for the strongest responders.
The researchers also found that more than 20% of treated participants, or 39 people, were in remission after 24 months — meaning their symptoms had improved to the point where they could function normally in daily life — a finding Conway said was particularly striking.
“We were shocked that one in five patients was effectively without depressive symptoms at the end of two years,” he said. “Seeing results like that for this complicated illness makes me optimistic about the future of this treatment. These results are highly atypical, as most studies of markedly treatment-resistant depression have very poor sustainability of benefit, certainly not at two years. We’re seeing people getting better and staying better.”
Reference: “Durability of the benefit of vagus nerve stimulation in markedly treatment-resistant major depression: a RECOVER trial report” by Charles R Conway, Augustus John Rush, Scott T Aaronson, Mark T Bunker, Charles Gordon, Mark S George, Patricio Riva-Posse, Rebecca M Allen, Ziad Nahas, Christopher L Kriedt, John Zajecka, David L Dunner, João Quevedo, Yvette Sheline, Walter Duffy, Brian J Mickey, Mary Stedman, Gustavo Alva, Lucian Manu, Quyen Tran, Charles F Zorumski, Matthew Macaluso, Michael Banov, Cristina Cusin, Jeffrey I Bennett, Hunter Brown, Jeffrey Way, Olivia Shy, Ying-Chieh (Lisa) Lee, Richard Hamish McAllister-Williams, Roger S McIntyre and Harold A Sackeim, 13 January 2026, International Journal of Neuropsychopharmacology.
This work was supported by LivaNova, PLC, the developer and manufacturer of the Vagus Nerve Stimulation therapy system. Conducting the study, analyzing the data, and drafting the report were supported by LivaNova, PLC. The U.S. Centers for Medicare & Medicaid Services approved the study under its NCD VNS for Treatment Resistant Depression. Final approval of the content of this manuscript and the decision to submit it were determined solely by the authors.
Conway has received research support from the American Foundation for Suicide Prevention, Assurex Health, August Busch IV Foundation, Barnes-Jewish Hospital Foundation, LivaNova, National Institute of Mental Health and the Taylor Family Institute for Innovative Psychiatric Research. He has also consulted for LivaNova.
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