Synopsis: Vagus nerve stimulation (VNS) has been available for decades for the treatment of seizures and more recently for the treatment of depression. This article explains the theory behind how VNS works, its outcomes for bipolar and unipolar depression and the potential downsides of the treatment.

BY LEN LANTZ, MD / 8.17.21; No. 50 / 8 min read

Disclaimer: Yes, I am a physician, but I’m not your doctor, and this article does not create a doctor-patient relationship. This article is for educational purposes and should not be seen as medical advice. You should consult with your physician before you rely on this information. This post might also contain affiliate links. Please click this LINK for the full disclaimer.

What is Vagus Nerve Stimulation?

Vagus nerve stimulation (VNS) uses a repetitive, mild electrical current to activate/depolarize the vagus nerve, which is the 10th cranial nerve, to change brain activity. Researchers have been exploring the modulation of the vagus nerve for decades to treat a variety of neurological and psychiatric conditions.

One of the most important breakthroughs in VNS research was the finding that stimulating the vagus nerve could help people with treatment-resistant seizure disorders. In 1997, the FDA approved the first VNS device by Cyberonics for the treatment of refractory epilepsy in adults and children as young as age 12. In 2017, LivaNova created a smaller VNS device that is now approved for refractory epilepsy for ages 4 and above. A metanalysis of the efficacy of VNS for treatment-resistant seizure disorders showed an impressive average reduction of seizures of 51% after 1 year of treatment (Englot, et al. Journal of Neurosurgery. 2011).

Another critical finding in VNS research was that stimulating the vagus nerve could help treatment-resistant depression. In 2005, the FDA approved a VNS device by Cyberonics for the treatment of severe, treatment-resistant unipolar and bipolar depression as an adjunctive treatment for people age 18 and older. In this approval, the FDA defined treatment resistance as having failed 4 or more antidepressant trials. In 2019, LivaNova’s device was approved for treatment-resistant depression for the same age range.

Why the Vagus Nerve?

The vagus nerve is one of 12 cranial nerves that leave the brain directly and do not rely on the spinal cord to send and receive nerve signals. It is the most complex, most extensive and longest cranial nerve, and it affects many bodily functions in the neck, chest and abdomen. The vagus nerve regulates heart and lung function, digestive function and aspects of neck function (swallowing and speech), among other roles.

While theories have been proposed, the mechanism by which VNS affects seizures and depression is not fully understood. VNS is a type of neuromodulation, meaning that it stimulates and changes brain activity. A layman’s understanding of the process is that stimulating the vagus nerve with tiny electrical impulses essentially calms down the brain. In addition to its current medical applications, researchers are using VNS to study or reverse engineer the brain to better understand the way it works and its changes during depression and epilepsy.

Details of VNS devices

VNS devices are small, pacemaker-like devices that are surgically placed under the skin on the left chest wall. The vagus nerve runs parallel to the carotid artery in the neck. A clamp is placed on the left vagus nerve and a thin wire is tunneled between the clamp and the VNS device. Placement is typically made by a neurosurgeon under general anesthesia, and most patients discharge home the same day as the surgery. The device is typically activated around 2 weeks after the surgery, and the battery life on the device is estimated to be 3 to 8 years.

The size of the Symmetry device (by LivaNova) is about that of two US quarters placed side by side. Other than rare risks from surgical placement, common side effects from VNS therapy are hoarseness or changes in voice, prickling or tingling in the skin, sore throat and shortness of breath. These side effects typically occur during the brief stimulation periods, which commonly are set to last 30 seconds followed by a 5-minute rest period (these parameters can be adjusted for each person after the device is placed).

The cost of VNS, including the device, surgery and hospital fees, was estimated at $30,000 by Inkwood Research, a Boston-based research firm (Dickson, V. Modern Healthcare. 2018).

The outcomes for depression

Most research on the efficacy of VNS for the treatment of depression is on implanted, also called invasive (iVNS), devices. Also, while the majority of research on VNS for depression includes bipolar and unipolar depression, most doctors mainly consider VNS for the treatment of bipolar depression. This might be due to the antiseizure properties of VNS, as anticonvulsants are used in the treatment of bipolar disorder, or because bipolar depression is often harder to treat. Many antidepressant medication treatments do not work well for bipolar depression, as antidepressants can lead to mood destabilization and overall mood worsening in bipolar disorder. There is a limited number of medications and medical interventions that help bipolar depression but do not lead to mood instability. That VNS has evidence for improving bipolar depression is a very significant finding, however, research to date on VNS for depression remains limited.

In a multicenter study in Europe, VNS was shown over 3 months to result in a response rate (depressive symptoms cut in half) of 37% and a remission rate (full freedom from depression) of 17%. After 1 year of treatment, the response rate climbed to 53% and the remission rate reached 33%. (Schlaepfer, et al. Psychological Medicine. 2008). Another study of VNS for depression found a response rate of 31% and remission rate of 15% after 3 months. After 1 year, the response rate increased to 44% and the remission rate to 27% (Nahas, et al. Journal of Clinical Psychiatry. 2005). In a 5-year observational study, people receiving VNS for depression had a 5-year cumulative response rate of 67% and a remission rate of 43%, both of which were significantly higher than those of the control group (Aaronson, et al. American Journal of Psychiatry. 2017).

Another important finding is that VNS for depression response and remission rates improve with time and show more gradual improvement than antidepressant, transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) interventions. While the majority of previous research on VNS outcomes for depression has been observational, there is an ongoing prospective, 5-year trial (RECOVER) that is randomized, controlled and blinded, and will shed more light on its efficacy (Conway, et al. Contemporary Clinical Trials. 2020). A separate study has already shown treatment durability at 1 year for bipolar and unipolar depression (Kumar, et al. Neuropsychiatric Disease and Treatment. 2017), and there also is a 5-year ongoing study (RESTORE-LIFE) that is evaluating the durability of response in VNS for treatment-resistant depression (Young, et al. BMC Psychiatry. 2020).

There also is a less invasive form of VNS called transcutaneous auricular vagus nerve stimulation (taVNS) that has convincing evidence of helping depression, but the device is not yet FDA approved for the treatment of depression. The taVNS device is an external (non-invasive) device that has a cord with ear clips. The taVNS can stimulate the vagus nerve by stimulating the surface of the ears. In a 12-week, nonrandomized, single-blind study of taVNS, researchers compared taVNS to sham treatment (a placebo). 138 patients completed the study, and by week 12, 39% of patients in the taVNS group achieved remission, compared to 17% in the sham group, and 80% of patients in the taVNS group achieved response, compared to 39% in the sham group (Rong, et al. Journal of Affective Disorders. 2016).

Will my health insurance cover VNS for depression?

Your health insurance might not cover the cost of VNS for depression. I recently reviewed the medical necessity criteria for the 5 largest private insurance companies in the US, and all covered VNS for refractory epilepsy but none covered VNS for depression. Most companies listed VNS as “investigational,” even though the FDA completed the investigation and approved VNS devices for depression 16 years ago. Unfortunately, calling an FDA-approved treatment investigational is a common tactic used by insurance companies to avoid spending money on medical care.

However, do not be discouraged! There is movement within the insurance companies. The Center for Medicare and Medicaid Services (CMS) has switched from noncoverage to conditional coverage of VNS for depression. Also, there is a possibility that if your insurance company does not cover VNS for depression, they may be violating your rights, breaking federal mental health parity laws and possibly violating your state’s mental health parity laws. To learn more about how to advocate for your rights in your mental health treatment, please read my article, “The Strengthening Behavioral Health Parity Act (SBHPA): An Enormous Step Forward in Mental Health Parity.” As the medical evidence base continues to grow in support of this treatment, health insurers will either decide to cover or be forced to cover VNS for depression.

What are the downsides of VNS for depression?

There are several possible downsides of VNS for depression. One of the most glaring downsides is limitations in the data proving its efficacy and cost. Both transcranial magnetic stimulation (TMS) therapy and electroconvulsive therapy (ECT) have far more data supporting efficacy, are less invasive than iVNS and are cheaper. A course of ECT generally costs $20,000 or less, a course of TMS often costs $10,000 or less, and most insurance companies cover both treatments.

Additionally, having iVNS in place is often a contraindication to receiving approval for TMS therapy. As the VNS clip on the vagus nerve is in the carotid sheath, there is a hypothetical risk that the magnetism from TMS therapy could disturb the clip and damage the carotid artery. Therefore, if a patient is considering both TMS and VNS for depression, they would be better off choosing TMS first and saving VNS as a possible treatment to access later. Additionally, recent research shows that TMS therapy can be extremely effective for depression. For additional details, read my article, “Stanford’s SAINT Study: a TMS Breakthrough for Depression?”.

There are other aspects of VNS that make it a more challenging solution for depression. One is that the battery will eventually need to be replaced, which will require additional surgical intervention. There also is the potential awkwardness of VNS affecting your voice during periods of vagus nerve stimulation. If stimulation begins while you are talking to someone, your voice may temporarily sound hoarse or your volume may drop suddenly, which may require you to explain what is causing unexpected changes in your speech.

What else is being researched with VNS?

Non-invasive VNS is being investigated to treat many conditions, however, FDA approval is limited. In 2018, the FDA approved a device by electroCore for the acute treatment of migraine headaches in adults. In 2021, the FDA approval for that device was extended down to age 12. In 2019, the FDA approved the electroCore device for the acute treatment of cluster headaches in adults. The VNS device by electroCore is an external device that stimulates the vagus nerve over the skin of the neck.

While not FDA-approved, Evren Technologies received a Breakthrough Device Designation in 2021 for their transcutaneous auricular vagus nerve stimulation (taVNS) device for the treatment of posttraumatic stress disorder (PTSD).

VNS is a promising option for treatment-resistant depression

People with treatment-resistant depression often experience a loss of hope that anything will work or that they will ever be free from the depression. It is important to remember that there are many advances in the treatment of depression, with ongoing research to support new options for patients or encourage researchers to explore other treatment areas. For new, evidence-based treatments, federal and state governments as well as elected and appointed judges must ensure that mental health parity law is being upheld so that citizens have access to critical treatment breakthroughs. While the evidence for VNS for depression appears positive, additional large-scale, placebo-controlled trials are needed to definitively prove its efficacy.

For further reading, check out:

• Len’s Article, “The Strengthening Behavioral Health Parity Act (SBHPA): An Enormous Step Forward in Mental Health Parity.”

• Len’s Article, “Stanford’s SAINT Study: a TMS Breakthrough for Depression?”

• Len’s article, “A Plan for Stubborn Depression”

• A Guide to Rational Living by Drs. Ellis and Harper (See Len’s Book Review)

• Mind Over Mood, Second Edition: Change How You Feel by Changing the Way You Think by Drs. Dennis, Greenberger and Padesky (See Len’s Book Review)

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