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Vagus Nerve Stimulation Helps Treatment-Resistant Depression

Treatment-resistant depression responds to vagus nerve stimulation, study finds.

This post is in response to
Vagus Nerve Stimulation Dramatically Reduces Inflammation
Sebastian Kaulitzki/Shutterstock
The "wandering" vagus nerve in yellow. 
Source: Sebastian Kaulitzki/Shutterstock

A landmark study has found that adjunctive vagus nerve stimulation (VNS) significantly improves treatment-resistant depression outcomes over a 5-year period. These findings were published July 1 in the American Journal of Psychiatry.

This study provides empirical evidence that VNS—which delivers mild electrical impulses to the vagus nerve via an implanted device—has robust antidepressant benefits when compared to a "treatment-as-usual" approach of medication, psychotherapy, and/or electroconvulsive therapy. Treatment-resistant patients receiving adjunctive VNS experienced higher rates of depression remission and symptom improvement when compared to patients only receiving traditional care. 

Why Does Vagus Nerve Stimulation Help Treatment-Resistant Depression?

Vagus means "wandering" in Latin. The vagus nerve is known as the "wandering nerve" because it has multiple branches that diverge from the brainstem and wander to the lowest viscera of your intestines touching your heart and most major organs along the way. As part of a gut-brain axis, the vagus nerve maintains a bi-directional feedback loop between your state of mind and what Claude Bernard would call your milieu intérieur (the environment within).

Your vagus nerve acts as a central command center for your parasympathetic nervous system (PNS) which regulates “rest-and-digest” or “tend-and-befriend” psychophysiological responses marked by positive emotions and feeling safe and sound. On the flip side, to maintain homeostasis, the sympathetic nervous system (SNS) drives the “fight-or-flight” mechanism and fuels stress responses marked by adrenaline and cortisol production in response to fear-based negative emotions, actual danger, catastrophizing, or a sense of uncertainty.

Based on today's current events, it's worth noting that the uptick of free-floating anxiety spawned by domestic political shenanigans and global uncertainty (triggered by such things as North Korea's intercontinental ballistic missile testing) can easily cause your fight-or-flight response to become hyperactive and run wild. Even if you don't suffer from clinical depression, making an effort to keep your vagus nerve engaged using holistic "vagal maneuvers"—such as diaphragmatic breathing and tonic levels of daily physical activity—is more important than ever. (To read more on this topic, check out my nine-part Psychology Today series "A Vagus Nerve Survival Guide to Combat Fight-or-Flight Urges"). 

Wellcome Library/Public Domain
Early anatomical drawing of the vagus nerve.
Source: Wellcome Library/Public Domain

In 1921, a Nobel Prize-winning German physiologist, Otto Loewi, made a happenstance discovery in his laboratory that would ultimately lead to the revelation that whenever someone takes a deep breath and exhales slowly—his or her vagus nerve squirts out a powerful "Xanax-like" substance that immediately slows heart rate and inhibits fight-or-flight nervous system responses. (This is why slow abdominal breathing makes you feel calm.) At the time, Loewi coined this vagus-produced tranquilizer vagusstuff (German for "vagus substance"). Vagusstuff proved to be the first neurotransmitter ever discovered and is called “acetylcholine” today. In the early 21st century, acetylcholine was identified as a key building block for a complex anti-inflammatory reflex that is enhanced by vagus nerve stimulation.

Higher vagal tone (VT) is linked to less inflammation, lower anxiety, better emotion regulation, and a wide-range of prosocial behaviors. Conversely, lower vagal tone is associated with systemic inflammation, anxiety disorders, clinical depression, and a wide range of other maladies. Therefore, it makes sense that stimulating the vagus nerve has the power to create an upward spiral of psychological and physical well-being.

In 1997, Mark George, of the Medical University of South Carolina (MUSC) in Charleston, was one of the first doctors to implant a VNS device for the treatment of depression. Since then, he's observed the long-term positive effects of VNS informally by staying in touch with dozens of patients. For example, he recently told Psychiatric News, "The patients by and large seem much more social and active than before. When you get questions such as, ‘Is it okay if I scuba dive with my VNS implant?’ it suggests the patient is doing well.”

In 2006, the U.S. Food and Drug Administration (FDA) approved VNS for the treatment of depression—but requested there be an ongoing surveillance study. This led to the creation of the "Treatment-Resistant Depression Registry" which has continuously tracked the outcomes of patients using vagus nerve stimulation compared to health outcomes of patients receiving traditional care for their depression.

As part of this registry, the recent 5-year study on the benefits of VNS was conducted across 61 different sites in the United States and included a total of 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) that had lasted continuously for at least two years; or patients who experienced three or more major depressive episodes (including the current episode) and hadn’t responded to four or more depression treatments (including electroconvulsive therapy).

Of the 705 study participants, 494 received a VNS implant in addition to their usual treatments, while 301 continued with treatment as usual—which included psychopharmaceuticals, psychotherapy, and/or ECT. In their latest paper, the authors describe the results of their ongoing study, "The adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6 percent compared with 40.9 percent ) and a significantly higher remission rate (cumulative first-time remitters, 43.3 percent compared with 25.7 percent)."

Alila Medical Media/Shutterstock
Source: Alila Medical Media/Shutterstock

Although this 5-year study identifies a correlation between VNS and significantly better treatment-resistant depression outcomes, the researchers are still unsure of causation. The million-dollar question remains, "Why does vagus nerve stimulation help depression?"

One hypothesis is that clinical depression may be linked to chronic activation of the "fight-or-flight" mechanisms of the sympathetic nervous system which perpetuates a complex chain reaction fueled by systemic inflammation and makes it difficult for brain cells to repair and recover consistently. Although much more research is needed before drawing any conclusions about the correlation between systemic inflammation and clinical depression, it is worth noting that vagus nerve stimulation dramatically reduces inflammation

In July 2016, an international team of researchers reported in the Proceedings of the National Academy of Sciences that vagus nerve stimulation reduced systemic inflammation and improved outcomes for patients with rheumatoid arthritis by inhibiting cytokine production. The neuroscientists and immunology experts involved in this study mapped the neural circuitry that regulates inflammation and found that action potentials transmitted in the vagus inhibited the production of pro-inflammatory cytokines.

The researchers believe that VNS could provide a potent and highly effective drug-free alternative for treating debilitating inflammation. Co-author of this study, Kevin J. Tracey, is president and CEO of the Feinstein Institute for Medical Research. He also discovered and coined the term "The Inflammatory Reflex." In a statement, Tracey said:

"This is a real breakthrough in our ability to help people suffering from inflammatory diseases. While we've previously studied animal models of inflammation, until now we had no proof that electrical stimulation of the vagus nerve can indeed inhibit cytokine production and reduce disease severity in humans. I believe this study will change the way we see modern medicine, helping us understand that our nerves can, with a little help, make the drugs that we need to help our body heal itself."

The growing body of research on using vagus nerve stimulation to help those with treatment-resistant depression and to downregulate the molecular expression of inflammatory cytokines offers tremendous promise. That said, more research and randomized, blinded, controlled clinical trials are needed before the general population should consider using various types of VNS implants as a routine part of depression management. But there is good news: The results of ongoing studies that will provide more finely-tuned best practices and other methods of VNS are on the horizon. Stay tuned! 


Aaronson, Scott T., Peter Sears, Francis Ruvuna, Mark Bunker, Charles R. Conway, Darin D. Dougherty, Frederick W. Reimherr, Thomas L. Schwartz, and John M. Zajecka. "A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality." American Journal of Psychiatry (Volume 174, Issue 7, July 01, 2017, pp. 640-648) DOI: 10.1176/appi.ajp.2017.16010034

Frieda A. Koopman, Sangeeta S. Chavan, Sanda Miljko, Simeon Grazio, Sekib Sokolovic, P. Richard Schuurman, Ashesh D. Mehta, Yaakov A. Levine, Michael Faltys, Ralph Zitnik, Kevin J. Tracey, and Paul P. Tak. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. PNAS, July 2016 DOI: 10.1073/pnas.1605635113