Vagus nerve stimulation offers new hope for treating severe depression

People with severe, treatment-resistant depression who underwent nerve-stimulating therapy experienced significant improvements in their symptoms, quality of life, and ability to carry out daily tasks after one year.

The research was focused on a large, multicenter clinical trial led by Washington University School of Medicine. 

Patients with treatment-resistant depression 

This national study, part of the RECOVER trial, involved nearly 500 participants at 84 sites across the United States. 

All were dealing with severe depression that had proven unresponsive to traditional treatments; on average, each had tried 13 unsuccessful therapies and had spent more than half of their lives living with this debilitating mood disorder. 

Many of the participants were so ill that they could not hold jobs or manage everyday activities. While this arm of the RECOVER trial focused on treatment-resistant major depression, the other arm addressing bipolar depression is ongoing.

“These patients are extremely ill, and most have been for a very long time,” said Charles R. Conway, principal investigator of the RECOVER trial and a professor of psychiatry at Washington University. 

“Despite that super-high level of sustained illness, we still see statistically significant, measurable improvements in depressive symptoms, quality of life, and functional outcomes.”

How vagus nerve stimulation works

The therapy at the heart of this trial is vagus nerve stimulation (VNS), which involves implanting a small, pacemaker-like device under the skin in the chest. 

A thin wire connects the device to the left vagus nerve in the neck – a major nerve that serves as a communication highway between the brain and the body’s internal organs. By sending mild electrical pulses through the nerve, the device stimulates areas of the brain involved in regulating mood.

Nearly two decades ago, the Food and Drug Administration (FDA) approved VNS therapy for treatment-resistant depression, but it never became widely available. 

Cost of vagus nerve stimulation 

The combined cost of the device and the implantation surgery can be substantial, and since the Centers for Medicare & Medicaid Services (CMS) and most private insurers do not cover it, many patients could not afford the therapy.

The RECOVER trial was designed in collaboration with CMS to generate data that might encourage coverage of VNS therapy for these severely ill patients. 

CMS provided some funding and helped plan the study, which aims to produce the evidence needed to determine whether to reimburse for the device and its surgical implantation. 

If CMS decides to cover the treatment, private insurance companies may follow suit, potentially making this therapy accessible to many more people.

“This study may help make this therapy more accessible,” Conway said. “If CMS decides to cover it, that will likely open the door for thousands of patients who have run out of other options.”

Inside the trial: Activated vs. inactive devices

In total, 493 participants were implanted with the VNS device. Roughly half – 249 people – had their devices turned on (activated) for the first 12 months of the trial, while the other half had implants that remained off during the same period. 

Throughout the trial, all participants continued their usual care for depression and kept seeing their mental health providers. They were discouraged from starting new antidepressants during the trial but were encouraged to maintain ongoing treatments.

Over the course of the year, the researchers regularly assessed the participants’ progress using multiple validated tools. 

Measuring changes in depressive symptoms 

Four well-established measures were used to gauge changes in depressive symptoms: two completed by off-site clinicians who were blinded to the treatment conditions, one by an on-site mental health professional, and one by the participants themselves. 

In addition, the participants provided self-reports of their quality of life and ability to perform daily activities every three months using three standardized quality-of-life tools and two functional assessments.

By examining various metrics, the researchers sought to understand how often participants experienced any relief of symptoms – even if temporary – and whether those improvements translated into tangible gains in their daily lives.

Significant improvements in daily functioning

After adjusting each device’s electrical parameters individually for the first two months, the investigators began measuring outcomes in month three and continued monthly evaluations for the remainder of the year. 

While the primary outcome measure – one particular assessment chosen as the trial’s main benchmark – showed no statistically significant difference between the activated and inactivated groups at the end of the year, many of the other measures told a more promising story.

Overall, individuals with active VNS therapy experienced more frequent improvements in their depressive symptoms than those whose devices were off. 

Vagus nerve stimulation and quality of life

Complete remission from depression was rare and did not differ significantly between the two groups, but people with activated devices reported feeling better more often. They also described meaningful gains in their quality of life and their ability to manage everyday tasks.

“They’re not just saying, ‘Yeah, I feel a little better,’” Conway explained. “They’re reporting that their lives are improving in real, tangible ways.”

“For a population that has been failed by a long list of treatments – including some of the most aggressive therapies like electroconvulsive therapy – even moderate improvements can be transformative.”

One reason the primary outcome measure may not have shown a clear difference is that the group with inactive devices improved more than expected as the trial reached its end. 

Conway noted that all participants knew the devices in the inactive group would be turned on at the end of the year, which may have given those participants hope and a positive psychological boost. This phenomenon could have reduced the contrast between the two groups on the primary measure.

Slow and steady gains

Another key observation was that most improvements became evident during the last three months of the 12-month trial. This timing aligns with prior research suggesting that VNS therapy’s benefits develop slowly over time. 

At the end of the year, the inactive devices were switched on, allowing those participants the opportunity to catch up with their counterparts who had been receiving stimulation all along.

“The nice thing about vagus nerve stimulation, we know from other studies, is that when the patient responds, the effects usually stick,” Conway said.

With a more extended follow-up planned – participants will be monitored for another four years – the researchers aim to see how these improvements hold up over time and whether they continue to grow. This long-term data will help them understand just how durable VNS benefits can be.

Looking toward the future

Beyond establishing the potential effectiveness of vagus nerve stimulation therapy for patients with treatment-resistant depression, the researchers hope to identify which individuals stand to benefit the most. 

Pinpointing characteristics tied to the best responses could help personalize this therapy, making it even more effective and efficient.

“We want to know who stands to gain the most,” Conway said. “If we can identify certain traits – such as specific clinical histories or patterns of treatment failures – that predict a good response, we might be able to tailor VNS therapy to the patients who need it most and are most likely to benefit.”

In the broader landscape of mental health care, these findings offer renewed hope. 

For decades, patients with severe, long-standing depression have had limited options after multiple therapies failed. VNS therapy, while not a cure-all, appears capable of delivering meaningful, lasting improvements to people who might otherwise remain stuck in severe depression.

“For these patients, even partial relief can mean the difference between being unable to get out of bed and being able to engage with life,” Conway said. 

“We’re hopeful that this study will ultimately help make vagus nerve stimulation available to more people who need it and provide them with a better chance at a more fulfilling life.”

The study is published in the journal Brain Stimulation.

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