About one in five adults in the United States will experience major depression at some point in their lives. Many people improve after trying a few treatments, but for as many as one-third of patients, standard antidepressants or psychotherapy do not provide enough relief. This condition, known as treatment-resistant depression, can persist for years or even decades. New research now suggests that a small implanted device may offer meaningful and long-lasting improvement for people with the most severe forms of the illness.

Scientists at Washington University School of Medicine in St. Louis led a large, multicenter clinical trial to evaluate this approach. The researchers found that a device designed to stimulate the vagus nerve was linked to sustained improvements in depressive symptoms, daily functioning, and overall quality of life. For most patients who showed improvement after one year, those gains continued for at least two years.

The participants in the study had lived with depression for an average of 29 years and had already tried about 13 treatments without success. These included intensive options such as electroconvulsive therapy and transcranial magnetic stimulation, highlighting just how difficult their condition had been to treat.

The latest results come from the ongoing RECOVER trial and were published Jan. 13 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."

How vagus nerve stimulation works

The RECOVER study was designed to test whether adding vagus nerve stimulation (VNS) to ongoing care could improve outcomes for people with treatment-resistant depression. The therapy involves surgically placing a device under the skin in the chest. The device sends carefully controlled electrical signals to the left vagus nerve – a key communication pathway between the brain and many internal organs.

The VNS Therapy System is made by LivaNova USA, Inc., which sponsored and funded the RECOVER trial. The study is collecting long-term data on mood, daily function, and quality of life in people with severe treatment-resistant depression. One aim of the research is to help the U.S. Centers for Medicare and Medicaid Services (CMS) decide whether to expand coverage for the therapy. Because many private insurers follow CMS decisions, approval could make the treatment accessible to far more patients, as cost has been a major barrier.

Inside the RECOVER trial

Nearly 500 patients were enrolled across 84 locations in the United States. About three-quarters of participants were so severely affected by depression that they were unable to work. All patients received the implanted device, but only half had the device activated during the first year to allow for comparison. Researchers tracked changes in depression severity, quality of life, and everyday functioning.

A response was considered meaningful if symptoms improved by at least 30% compared with the start of the study. A reduction of 50% or more was classified as a "substantial" response.

Conway emphasized that even modest improvements can dramatically change a person’s life. Severe depression can leave people feeling "paralyzed by life," unable to manage basic daily activities and at higher risk of hospitalization or early death.

Earlier findings from the blinded first year of the trial showed that patients with activated devices spent more time with improved mood, better functioning, and higher quality of life than those whose devices were not active. However, the primary measurement tool (the Montgomery-Åsberg depression scale, which measures the severity of depressive episodes) did not show a statistically significant difference between the two groups.

Benefits that last over time

In the newest analysis, the researchers focused on patients whose devices were active from the start of the trial. They wanted to see whether improvements seen at 12 months would continue through 24 months. They also examined whether some patients who did not improve in the first year might respond later with continued treatment.

Out of 214 patients who received active treatment from the beginning, about 69%, or 147 people, showed a meaningful response at one year in at least one outcome measure. Among those who benefited at 12 months, more than 80% maintained or improved their results by the two-year mark across measures of depression, quality of life, and daily functioning. For patients with a substantial response at one year – defined as at least a 50% reduction in symptoms – 92% were still benefiting at two years.

Nearly one-third of participants who had not improved after the first year reported benefits by the end of the second year, suggesting that the therapy may take longer to work for some individuals. Relapse rates remained low among those who responded, particularly among the strongest responders.

The researchers also found that more than 20% of treated patients, or 39 people, were in remission after 24 months. This means their symptoms had eased enough for them to function normally in daily life, a result Conway described as especially notable.

"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."

Funding and disclosures

The study was supported by LivaNova, PLC, the developer and manufacturer of the Vagus Nerve Stimulation therapy system. LivaNova, PLC supported the study design, data analysis, and preparation of the report. The U.S. Centers for Medicare & Medicaid Services approved the study under its NCD VNS for Treatment Resistant Depression. The authors alone made the final decision on the manuscript content and its submission for publication.

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 served as a consultant for LivaNova.