Preliminary Results from RESTORE-LIFE Shows Promise for VNS in Difficult to Treat Depression

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Preliminary findings from the RESTORE-LIFE study (NCT03320304) show long-term effectiveness of vagus nerve stimulation (VN) in patients with difficult-to-treat depression (DTD). The global, prospective, multi-center, observational study is assessing the long-term effectiveness and safety of VNS as an alternative treatment in patients with DTD.

Patients (n=100) in this analysis included in the study ranged from ages 22 to 79, with primary diagnoses of chronic or recurrent major depressive episode; 78% of patients had unipolar depression and 22% had bipolar depression. Study response was defined as at least a 50% reduction on the Montgomery-Asberg Depression Rating Scale from baseline (MADRS). Most patients had previously received either electroconvulsive therapy (61%) or transcranial magnetic stimulation (26%).The ongoing study has an inclusion goal of at least 500 patients for an observation period of 60 months after baseline.

Daily charge delivered was compared at 12-month for patients whose symptoms responded to VNS compared to non-response to the treatment. Regression models were used to investigate the relationship between VNS dosing parameters and mean MADRS reduction. Follow-up visits were scheduled in 3-month increments for the first 18 months; visits will be scheduled every 6 months after that point. Variables assessed included change from baseline MADRS, baseline output current and total change per day, the visit level output current, and total charge per day, age, sex, and visit.

The researchers found that in the long-term, VNS was relatively effective, with a cumulative response rate of 52.8% after 12 months. They observed higher total daily charge at 12 months in patients with symptoms that did not respond versus those whose symptoms did respond. The preliminary data failed to find a statistically significant relationship between VNS titration and MADRS reduction at the 12 month mark. They noted that older patients (>65 years) and those with greater depression severity demonstrated significantly greater decreases in mean MADRS scores.

In assessing safety, the preliminary study data indicated that VNS was well tolerated. Compared with previous meta-analysis that found about 70% of patients experiences stimulation-related side-effects in the long-term course, data indicated only 47% of participants experienced adverse events. The dropout rate was similarly low at 11% (compared with 20% in previous analysis), and most reported effects were transient in nature.

The researchers noted that a longer observation period may be needed to truly evaluate the VNS daily charge efficacy.

“DTD is a disabling disease, which is associated with chronic and multiple episodes in early decades of life, increased healthcare utilization, high risk of suicidality as well as impaired quality of life and functioning,” the author wrote. “Further studies are needed to evaluate the impact of different levels of daily charge on response in VNS. Given the delayed onset of antidepressant efficacy of VNS, the investigations on the relationship between daily charge delivered and response rate may reveal clearer results in the subsequent years.”

Reference

1.Kavakbasi, E, Kraus, C, et al. Titration of vagus nerve stimulation for difficult-to-treat depression and onset of response: Early insights from the RESTORE-LIFE study. J Affect Disord. 2025;378:39-46.