A national, multicenter clinical trial led by Washington University School of Medicine in St. Louis indicates that vagus nerve stimulation (VNS) therapy can significantly improve depressive symptoms, quality of life, and the ability to perform daily tasks in individuals with severe, treatment-resistant depression. The study, involving nearly 500 participants across 84 U.S. sites, offers renewed hope for those who have not found relief through conventional treatments. The findings were published in a pair of papers in the journal Brain Stimulation on December 18, 2024.
Key Findings from the RECOVER Trial
The RECOVER trial included participants with severe depression that had not responded to medication or other therapies. A significant portion of participants (75%) were unable to work due to their condition, and 40% had a history of suicide attempts. Each participant received an implanted device to stimulate the left vagus nerve, but only half of the devices were activated during the 12-month randomized control period.
While the primary outcome measure, the Montgomery-Åsberg Depression Rating Scale (MADRS), did not show significant differences between the active and inactive VNS groups, secondary measures revealed notable improvements in depressive symptoms, daily functioning, and quality of life. These improvements were based on ratings from on-site clinicians, patients, and independent off-site raters who were unaware of device activation status.
Expert Commentary
"These patients are extremely ill, and most have been for a very long time," said Charles R. Conway, MD, professor of psychiatry at WashU Medicine and principal investigator of the RECOVER trial. "On average, each patient had already tried 13 treatments that failed to help them before they enrolled in the trial, and they had spent more than half of their lives sick with depression. But despite that super-high level of sustained illness, we still see statistically significant, measurable improvements in depressive symptoms, quality of life, and functional outcomes."
Mechanism of Action and Clinical Significance
Vagus nerve stimulation involves the surgical implantation of a device that delivers electrical pulses to the left vagus nerve, which connects the brain to various internal organs. This stimulation targets brain regions involved in mood regulation, such as the amygdala and prefrontal cortex. The therapy has shown potential in reducing depressive symptoms and enhancing overall quality of life.
Unlike medications that affect the entire brain, VNS delivers focused stimulation to mood-regulating brain regions and can be used alongside other treatments. This offers additional relief for those who do not fully respond to antidepressants or therapy. The effects of VNS tend to be gradual, with most improvements observed in the final three months of the trial.
Implications for Treatment Access
Despite being approved by the FDA for treatment-resistant depression nearly two decades ago, VNS has not become widely available due to its cost and lack of insurance coverage. The RECOVER study was designed to gather data that could persuade the Centers for Medicare and Medicaid Services (CMS) to cover the therapy, potentially making it accessible to more patients. CMS helped design the RECOVER study and provided some funding.
Study Limitations and Future Directions
One limitation of the study was that the primary outcome measure did not show significant differences between the active and inactive VNS groups. This may be due to a higher-than-expected placebo effect in the inactive group, as participants knew that their devices would be activated at the end of the 12-month control period. The participants will be followed for another four years to determine the long-term effects of VNS and to identify patient characteristics associated with the greatest response.
