In patients with marked treatment-resistant depression (TRD), adjunctive vagus nerve stimulation (VNS) demonstrated sustained benefits in symptom, function, and quality of life (QOL) through 24 months, with low relapse rates.

Furthermore, approximately 80% of participants who achieved clinically meaningful improvements at 12 months maintained these benefits at 24 months.

In addition, a subset of participants who did not achieve meaningful benefit at 12 months did so by the end of the second year; overall, more than 20% of participants were in remission at 24 months.

Given the study’s exceptionally treatment-resistant population, “the durability of benefit was exceptional,” the investigators, led by Charles R. Conway, MD, professor of psychiatry and director of the Washington University Resistant Mood Disorders Center in St. Louis, wrote.

“There is a dire need to find effective treatments for these patients, who often have no options,” Conway said in a press release. “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.”

The results were published online on January 13 in the International Journal of Neuropsychopharmacology.

Highly Resistant Population

VNS involves implanting a small device under the skin in the chest and attaching it to a wire that emits electrical pulses to the vagus nerve. A key part of the parasympathetic nervous system, this nerve carries signals between the brain, heart, and digestive system.

This treatment has demonstrated meaningful and durable antidepressant effects in major depression. Prior trials showed that approximately 40%-50% of patients with marked TRD achieved meaningful improvement 3-12 months after initiation, reflecting a longer time to benefit than is typical with other antidepressant treatments.

The observational study included 214 adults with severe TRD (mean age, 55.2 years; 68.2% female), who were originally randomly assigned to the VNS arm of the large multisite RECOVER trial. This blinded study compared 12-month outcomes of active VNS vs sham stimulation, combined with treatment as usual.

The study sample is likely the most resistant ever studied in a randomized controlled trial, the investigators noted. Participants had a mean of 13.5 failed antidepressant treatment trials, and most had insufficient benefit from neurostimulation treatments. In addition, participants were severely affected by depression. Approximately 75% were so ill they were unable to work.

At the end of the original trial, those in the treatment arm received active VNS for an additional 12 months.

Outcomes at 18 and 24 months were assessed using seven measures covering depressive symptoms, global improvement, functioning, and QOL. Recognizing that traditional depression trials focus narrowly on symptom change, the investigators emphasized functional and quality-of-life outcomes, which are often profoundly impaired in these patients.

Outcomes were categorized as no meaningful benefit, meaningful benefit, substantial benefit, or remission; for symptom measures, meaningful benefit reflected partial response (≥ 30% reduction), and substantial benefit reflected response (≥ 50% reduction).

The investigators noted that a ≥ 50% reduction is relatively rare in patients with markedly TRD. Research shows a lesser degree of improvement such as a ≥ 30% reduction can indicate improvement.

Sustained Benefit

At 12 months, 43.6% vs 80.0% of participants achieved at least meaningful benefit on the Montgomery-Åsberg Depression Rating Scale (MADRS) vs on the tripartite composite measure.

Benefit was largely sustained during the second year of stimulation. Across all seven outcome measures, more than 80% of participants who achieved clinically meaningful benefit at 12 months maintained that benefit at both 18 and 24 months, with median durability rates of 83.1% and 81.3%, respectively.

On individual measures, the proportion of participants achieving meaningful benefit or greater on the MADRS increased by 9.9 percentage points from 12 to 24 months (95% CI, 2.9%-17.0%; P = .007). A similar pattern was observed on the Clinical Global Impression-Improvement scale, with second-year increases of 8.6 percentage points for meaningful benefit or greater and 10.8 percentage points for substantial benefit.

Using the tripartite composite metric, 80.0% of participants achieved meaningful benefit or better at 12 months; this proportion increased to 83.6% at 18 months and remained high at 82.4% at 24 months. Although remission is relatively uncommon in markedly TRD, 21.5% of participants met remission criteria on the MADRS at 24 months, representing a significant increase compared with 12 months.

“We were shocked that 1 in 5 patients was effectively without depressive symptoms at the end of 2 years,” said Conway in the release. “Seeing results like that for this complicated illness makes me optimistic about the future of this treatment.”

Many participants with no meaningful benefit at 12 months achieved it at 18 months (median, 30.6%) and 24 months (median, 37.8%), suggesting that VNS might take more time to work in some patients.

Analyses of concomitant medication use during the second year, as well as exposure to electroconvulsive therapy, transcranial magnetic stimulation, or ketamine and esketamine, did not indicate that these treatments accounted for the durability of benefit observed with VNS.

Given that most studies in markedly TRD show poor durability of benefit — particularly at 2 years — the findings are “highly atypical,” said Conway. “We’re seeing people getting better — and staying better.”

New Hope for TRD

Commenting on the findings for Medscape Medical News, Susan K. Conroy, MD, PhD, assistant professor of psychiatry and adjunct assistant professor of neurological surgery, Indiana University School of Medicine, Indianapolis, said the findings are “impressive.”

“For a long time, we’ve been trying to figure out what the place of vagus nerve stimulation is in the TRD armamentarium, and this study continues to suggest that VNS definitely helps people with very long-standing, very treatment-resistant depression.”

She noted the importance of the finding that many participants who did not benefit at 12 months experienced substantial improvement during the second year of treatment.

“It’s really hard to hang in there for 2 years if you’re the one suffering from depression, but this offers some measure of hope for people with that kind of chronic illness,” she said.

Another key finding from the study is that “people who do get better with VNS tend to stay better,” and that this durability is independent of other treatments patients may be receiving, said Conroy.

She hopes the new findings will help make VNS more acceptable to patients who may be hesitant because it involves surgery. “People hear the word surgery and think something drastic, but this is actually a simple, very brief outpatient procedure,” she added.

The study received funding from LivaNova PLC, the developer and manufacturer of the vagus nerve stimulation system used in the study. Conway reported receiving research support from the American Foundation for Suicide Prevention, Assurex Health, August Busch IV Foundation, Barnes-Jewish Hospital Foundation, LivaNova PLC, National Institute of Mental Health, and the Taylor Family Institute for Innovative Psychiatric Research. He reported having also consulted for LivaNova PLC.