How stimulating the body’s largest nerve may relieve severe depression

By Kristen Rogers, CNN

(CNN) — Nick Fournie was 24 years old when severe depression upended his life.

Fournie had been married to his longtime sweetheart for two years, and had no reason to suspect he had any mental health issues.

“I just thought to myself, ‘If this is it, if this is all there is to life — if it ended now, I’d be OK with it,’” Nick, now 62 and based in Illinois, said of that fateful day outdoors nearly 40 years ago.

But one day as he was mowing the lawn, his perspective on life abruptly flipped from light to dark. The shift would set him and his wife, Mary, on a tumultuous, yearslong journey of fighting for his well-being and another chance at a happy life together — until they learned of an alternative, obscure treatment that would change everything.

Over the next decade, Nick worked with a psychiatrist to find a medication that would alleviate his depression. Not only did the 10 or so drugs he tried fail to improve his condition — they also caused “terrible reactions,” Mary said, especially when he was prescribed more than one drug at once.

Nick has always been sensitive to medications, but he likened the side effects he experienced to “psychotic episodes.” Although he believed the psychiatrist was doing his best, “some of (the drugs) really sent me way out of my mind,” he said.

On some days he wasn’t functioning, and even experienced paranoia that kept him from leaving the house, Mary said.

Nick was generally able to keep working but couldn’t feel happiness about anything, he said. “Every single day seemed like it was two days.”

Nearly 20 years ago, knowing all other options had failed, Nick’s sister, a nurse, recommended he check out a new treatment called vagus nerve stimulation, or VNS. The US Food and Drug Administration had just approved VNS in 2005 for the long-term adjunctive treatment of chronic or recurrent depression in adults who had had inadequate responses to at least four antidepressant treatments.

“The vagus nerve is the largest nerve in your body,” said neuroscientist Dr. Bashar Badran, associate professor of psychiatry and director of the Neuro-X Lab at the Medical University of South Carolina in Charleston. “It has over 100,000 individual nerves in a bundle.

“This bundle projects from your brain to every organ in your body, like your heart, your lungs, your spleen, your kidneys, your intestines,” he said. “The vagus nerve is this bidirectional superhighway that relays information from your brain to your body.”

Nick soon enrolled as a participant in a VNS trial led by Dr. Charles Conway and had a VNS device implanted.

“It’s a very small pulse generator that’s similar to a cardiac pacemaker,” said Conway, professor of psychiatry and director of the Center for the Advancement of Research in Resistant Mood and Affective Disorders at Washington University in St. Louis.

The device is implanted underneath the collarbone, and a lead from the device is tunneled to the neck region, where it attaches to and stimulates the vagus nerve that, in turn, sends regular pulses to areas of the brain associated with mood regulation. The standard firing rate is 30 seconds every five minutes.

Nick remains on VNS treatment to this day in addition to being on two antidepressants he alternates using with his doctor’s instructions, depending on which one s working for him. “It completely changed my life. I find joy every single day,” he said.

“If it was just only medication, I don’t know that he would be alive today,” Mary said. “I tell Dr. Conway all the time, this was a miracle for us. Not to say that you don’t also have to do some behavior modifications, and you have to learn coping techniques and all that. It isn’t this magic bullet. It’s work, (but) it has saved our lives together, and his life.”

Despite the FDA’s approval of VNS treatment for treatment-resistant depression, in 2007, the US Centers for Medicare & Medicaid Services declined to insure the therapy, citing its conclusions that evidence was insufficient and that VNS was “not reasonable and necessary” for the condition. The CMS decision also had an impact on private insurance companies, many of which aligned themselves with the agency’s stance, Conway said.

Subsequent studies provided additional support for VNS, prompting the CMS to decide in 2019 to issue “coverage with evidence development.” This move made VNS accessible to people participating in a trial designed by the FDA-approved VNS device manufacturer, LivaNova, and approved by CMS.

The results of that randomized clinical trial, conducted at 84 sites in the United States from September 2019 to May 2024, are now presented in two studies published Wednesday in the journal Brain Stimulation. LivaNova sponsored and funded the studies in partnership with CMS.

The yearlong trial of 493 adults with an average age of 53 mirrors Nick’s experience — it found VNS therapy led to improvement in participants’ depressive symptoms, ability to complete daily tasks and quality of life.

The population studied “was probably the sickest group of treatment-resistant depression patients ever studied,” said Conway, who was also lead investigator of the latest trial. “They had an average of 13 failed treatments, and the mean number of years that they had spent in depression was 29 years.”

About 75% of these participants had been so ill they were unable to work, and 40% had previously attempted suicide at least once.

“What’s really important here is that the patients themselves were reporting that their lives were improving,” Conway said in a news release. “And the nice thing about vagus nerve stimulation, we know from other studies, is that when the patient responds, the effects usually stick.”

Relieving severe depression

At the study’s outset, all participants were implanted with vagal nerve stimulators. After two weeks of recovery from surgery, half the participants had their devices turned on, while the stimulators in the other half, essentially a control group, were left off. Regardless of which group they were in, all participants remained on whatever treatment they had already been on, including drugs, therapy or both.

“Then we gave them two months to, what we call, titrate up their current,” Conway said. “A certain amount of current is optimal for getting an antidepressant response.”

Over the next 10 months, the adults participated in monthly evaluations of their depression symptoms, quality of life and other functional outcomes. The trial didn’t meet its primary goal, which was for the Montgomery-Asberg Depression Rating Scale, or MADRAS, to show more improvement in the active VNS group than in the inactive VNS group. But in judging the results in both groups according to this scale, there were no differences between the two.

The MADRAS scale is one of the gold standard scales for evaluating individual symptoms that combine into depression, said Badran, who wasn’t involved in the study. It includes factors such as mood, sleep, appetite and energy level.

“They allow for a more nuanced assessment of depression severity because it’s administered by a clinician,” Badran said. “It’s kind of a bummer to see that the primary endpoint failed to meet that significance.”

The study, however, met its secondary goals — which included improvements in depressive symptoms, daily function and quality of life, according to three other rating scales reported by on-site clinicians, patients and offsite raters who weren’t privy to which participants’ devices had been activated.

Overall, 18% of active VNS patients experienced symptom improvement by at least 50%, Conway said, which is considered a full response to treatment. Regarding quality of life, 53% of the active treatment group experienced progress.

The tendency of clinical trials to meet only secondary outcomes isn’t uncommon, Badran said. “Not all studies have to hit on their primary (goal) to demonstrate some sort of efficacy,” he added.

Most of the benefits were observed in the final three months of the 10-month treatment period, which wasn’t surprising or concerning since VNS treatment works cumulatively, experts said.

What was surprising was that 16% of those in the inactive VNS group also reported antidepressant effects in the last few months, whereas the researchers had expected only around 10% of these participants to do so.

“Participants may have been positively anticipating device activation at the 1-year time point, or ‘placebo’ effects were accentuated by foreknowledge of the trial duration and awareness that benefits typically accrue with VNS only after several months of treatment,” according to the study. The inactive group’s devices were turned on at the end of the trial so they, too, could hopefully benefit.

With treatment-resistant depression affecting about 30% of an estimated 21 million adults with major depressive disorder, the findings are “really promising,” Badran said.

The new research also carries substantially more significance than previous studies due to its large-scale recruitment and long-term follow-up, said Dr. Takuya Sasaki, professor of life and pharmaceutical sciences at Tohoku University in Japan, via email. Sasaki wasn’t involved in the study.

The research “provides a sham-controlled, blinded comparison of how well VNS works for (treatment-resistant depression) in a rigorous study design,” said Dr. Sarah Lisanby, director of the Noninvasive Neuromodulation Unit of the Division of Intramural Research Program at the US National Institute of Mental Health, via email. Lisanby also wasn’t part of the research team.

The shortcomings and inner workings of VNS

That the study’s primary endpoint wasn’t met and only up to 53% of the active VNS participants experienced improvements may be due to a few factors.

The severity of depression in this trial “likely limited the possibility of response and remission in both groups,” the authors said. “To our knowledge, the degree of resistance in this trial exceeds any previous large, prospective, antidepressant therapeutic trial.”

Additionally, having hundreds of patients in a clinical trial can also mean they’re not the most uniform in terms of their illness case, Badran said. Some people may not respond at all, while others fare quite well.

On a positive note, the extent of resistance may also imply that patients with less resistance could benefit from VNS more, the authors added.

Vagal nerve stimulation implants can sometimes cause side effects, such as shortness of breath, site irritation or vocal hoarseness when the device is on, experts said.

Knowledge of all the ways by which VNS improves depression is still evolving, but the therapy likely works through multiple pathways, experts said.

“If we look at VNS as a modulator of the central nervous system in the brain, there’s evidence to suggest that when you turn VNS on, you’re influencing the default mode network,” Badran said. “This network is involved in emotion, mood and self-processing.”

Our fight-or-flight response is mediated by the vagus nerve, which releases the neurotransmitter acetylcholine onto agitated organs to slow them down, Badran said.

Vagus nerve stimulation can also increase the release of important brain chemicals such as serotonin and norepinephrine, which help regulate mood and are typically low in people with depression, Sasaki said.

“The vagus nerve also helps control inflammation in the body,” higher levels of which have been linked to depression, Sasaki added. The treatment may help the brain become more adaptable and resilient by promoting the formation of new brain connections as well.

The future of treating resistant depression

The trial participants continue to be monitored, and data on their ongoing results may become available over the coming years.

Conway plans to continue discussions with the Centers for Medicare and Medicaid Services based on the trial results in hopes the findings will eventually help people with treatment-resistant depression and federal health insurance to be able to receive VNS therapy, he said.

Accessibility of VNS treatment is still limited due to the roughly $25,000 price tag and the lack of coverage by federal insurance and by many private insurers, experts said.

If you’re interested in trying VNS, you can inquire about private insurance coverage by calling your insurer or talking to your employer, which is what Mary did when Nick needed a device replacement due to a complication.

If you’d like to participate in a clinical trial, talk to your doctor or psychiatrist to see if that’s an option for you, said Dr. Nils Kroemer, a professor of medical psychology at the University of Bonn in Germany, via email. Kroemer wasn’t involved in the study.

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