Stimulating a Nerve: The Long, Winding Road of Vagus Nerve Stimulation as a Treatment for Treatment-Resistant Depression

The FDA has approved vagus nerve stimulation for depression for people for whom other treatments have failed, but its use has been limited partly for lack of insurance coverage. That may change if results from a large, industry-sponsored randomized trial are positive, although the wait for those results might be a long one because the researchers are still recruiting patients.

The vagus nerve is longest of the 12 cranial nerves that travel from the brain — specifically the medulla oblongata ‚ and then has multiple branches that go to the larynx, esophagus, heart, lungs and organs of the digestive tract. It carries both efferent motor signals away from the brain and afferent, sensory ones toward it. The vagus nerve is a crucial part of the parasympathetic nervous system that is often described as controlling the “rest and digest” response, which involves a slowing down of the heart, dilatation of the blood vessels, increased flow of digestive fluids and relaxation the muscles of the gastrointestinal tract.

Vague nerve stimulation, which has a history dating back to the late 19th century, is true to the name: It involves administration of mild electrical pulses to stimulate the vagus nerve. Invasive or implanted vagus nerve stimulation devices consist of a pulse generator implanted in the chest wall, an electrode cuff around a branch (typically the left one) of the vagus nerve in the neck and a wire connecting the two. Vagus nerve stimulations have been compared to pacemakers the heart.

More recently, researchers and device companies have developed noninvasive devices that deliver the electrical stimulation through the skin. Patients can administer noninvasive vagus stimulation themselves and at home.

The FDA has also approved vague nerve stimulation as a treatment for epilepsy and for rehabilitation from stroke, and it is being actively investigated as a treatment for many other conditions, ranging from pain to obesity to headache.

A review of vagus nerve stimulation advances published in the journal Clinical Autonomic Research in October 2024 identified a study led by August John Rush, M.D., then at the University of Texas Southwestern Medical Center, as the first open-label pilot trial of invasive vagus nerve stimulation as the treatment for treatment-resistant depression. According to first author Christopher W. Austelle, M.D., a postdoctoral scholar at Stanford, the study included 40 patients with a history of major depressive disorder or bipolar disorder for whom medications hadn’t worked. After three months, 40% of the patients had at least a 50% reduction in depressive symptoms. An extension trial showed that the response was sustained and remission in a sizable proportion (29%) of patients. The results were published in 2000 in the journal Biological Psychiatry.

Austelle and his co-authors credit Rush with leading the only randomized, sham-controlled trial of invasive vagus stimulation for depression. A total of 235 people with depression that had not responded to other treatments were randomly assigned to active or sham treatment. The results, reported in Biological Psychiatry in 2005, were disappointing for those hoping that this more rigorously design trial would tip the balance in favor of vagus nerve stimulation as a treatment for hard-to-treat depression. After 10 weeks, Rush and his colleague found no difference in the response rates between those in the active group and those in the shame one. Austelle and his colleagues say that outcome might be explained by 10 weeks not being enough time for vagus nerve stimulation to have an effect.

Still, the FDA approved vagus nerve stimulation as a treatment for treatment-resistant depression in 2007 based on evidence of a trial comparing usual treatment with addition of invasive vagus nerve stimulation with usual treatment alone. Mark S. George, M.D., of the Medical University of South Carolina, was the lead author of the paper reporting the results of that study, which were also published in 2005 and also in Biological Psychiatry. Rush was listed second among the authors.

Notwithstanding the imprimatur of FDA approval, Austelle and his colleagues say that access to invasive vagus nerve stimulation for treatment-resistant depression has been curtailed because CMS decided not to cover it, in part because of the unfavorable results from the sham-controlled trial led by Rush. Also, commercial insurers often follow CMS’ lead in their coverage decisions.

They see the RECOVER trial as perhaps providing the evidence that will lead to Medicare and commercial insurance coverage and bring invasive vagus nerve stimulation more into the mainstream of depression treatment. Their exact words: “If positive, this trial would likely provide the evidence needed for CMS and other insurance companies to cover iVNS [invasive vagus nerve stimulation] for TRD [treatment-resistant depression].”

The trial is sponsored by LivaNova, an Italian and American medical technology company headquartered in London that, among its other products, makes an invasive vagus nerve stimulation device.

On clinicaltrials.gov, is described as a prospective multicenter, randomized, controlled, blinded trial of subjects implanted with vagus nerve stimulation. It is labeled as still recruiting patients. Total enrollment is listed as 6,800, but 5,800 are to be enrolled directly into the open-label phase, suggesting that the investigators are aiming to enroll 1,000 patients into initial randomized trial. The researchers are randomly assigning them to active treatment or no stimulation at least two weeks after implantation of the device and then observing them for a year. Austelle and his colleagues say one of the crucial differences between the RECOVER trial and the one conducted by Rush approximately 20 years ago is that the response to vagus nerve stimulation will be measured after a year, not just 10 weeks. They say that various threads of evidence suggest that the response to vague nerve stimulation tends to be gradual, so a yearlong trial is a better way to assess it.

According to the description on clincialtrials.gov, after completing the 12 month end point in the randomized phase of the study, all the participants will transition to a prospective, open-label, longitudinal study, and people in the control arm will receive active treatment.

The researchers are also planning on enrolling 5,800 new subjects directly into the open-label phase of the study with the goal of having them participate in the study for approximately five years, according to the clinicaltrials.gov entry about the trial.

The trial appears to be moving slowly, however. It had an official start date in September 2019 and “primary completion” is scheduled for February 2028 and completion not until 2031.