VNS Therapy has been approved by the US Food and Drug Administration (FDA) for over 2 decades. It’s backed by multiple clinical trials, including the largest randomized controlled trial (RCT) in difficult-to-treat depression (DTD).^1-4

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We’ve measured depression treatment success the same way for decades: symptom rating scales. But what if that’s not enough?

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The RECOVER trial (1, 2) showed significant improvements in quality of life and function, even when traditional symptom measures told a more modest story.^4,5

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For patients who have failed 4 or more antidepressant treatments, many of whom have also tried electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS), those quality of life and functional gains aren’t secondary. They’re the whole point.

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Watch the recording with Dr. Hamish McAllister-Williams from the Northern Centre for Mood Disorders at Newcastle University as he discusses the latest evidence for VNS Therapy in DTD, including results from the RECOVER trial. Hosted by Dr. Will Sauvé, Chief Medical Officer at Osmind.

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What You Will Learn:

• The concept of DTD and its treatment goals
• Why symptom improvements alone don’t capture the full picture of recovery
• Key findings from the RECOVER trial on VNS Therapy
• How quality of life and function improved even when symptom response was modest
• Which patients showed the strongest differential benefit

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Understanding DTD

DTD at its most basic level is depression that continues to cause significant burden despite usual treatment efforts.⁶ Generally, this includes patients who have been unable to achieve response/remission, sustain response/remission, or tolerate treatment.⁶ While the ultimate goal for treating depression is to achieve remission, in patients with DTD the management goals are broadened to include striving for optimal symptom control (remission if possible), reducing the risks and impact of relapse, and optimizing psychosocial functioning.⁶ 

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Here’s how disconnected our measurements are from patient experience: in one study, only 55% of patients who met criteria for remission on rating scales actually felt they were in remission.⁷ Patients who self-reported nonremission, despite being in clinical remission, reported reductions in psychosocial function and quality of life as to why they did not feel they were in remission.⁷ What clinicians measure and what patients experience aren’t the same thing.

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Headlines Don’t Tell the Whole Story of RECOVER. Additional Symptom, Function, and Quality of Life Measures Show Clear Benefit.

RECOVER enrolled 493 patients with DTD—the largest RCT in this population.⁴ Patients were randomized to active VNS Therapy plus treatment as usual (TAU) versus sham stimulation plus TAU for 12 months.⁴

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These weren’t typical research participants. Mean depression severity was firmly in the severe range (Montgomery-Åsberg Depression Rating Scale [MADRS] score of 34).⁴ Eighty percent were rated as markedly ill or worse (using the Clinical Global Impression–Severity). Current episode duration averaged 17.8 years.⁴ Half had tried ECT, with 75% of those failing to respond.⁴ Fifty percent had tried TMS in the current episode.⁴ Twenty-five percent had tried esketamine in the current episode.⁴

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The primary endpoint: Percent time in MADRS response from months 3 through 12.⁴

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The result: The trial missed statistical significance on the primary endpoint.⁴ Percent time in response on the MADRS was higher in the VNS Therapy group but was not enough to clear the P<0.05 threshold.⁴

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VNS Therapy did reach statistical significance for other symptom-based measures, such as the Quick Inventory of Depressive Symptomatology–Clinician (partial response), Quick Inventory of Depressive Symptomatology–Self-Report (response), and Clinical Global Impression–Improvement (CGI-I) (partial response, response, and remission).⁴ 

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Quality of Life Improved. Function Improved. The Gains Lasted.

Quality of life and function showed clear separation. The Quality of Life Enjoyment and Satisfaction Questionnaire and the Work Productivity and Activity Impairment Questionnaire item 6 demonstrated statistically significant improvements in the VNS Therapy group, crossing the threshold for clinical meaningfulness.⁵ 

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A new metric to capture the improvements that matter to patients.

The tripartite metric was developed to identify clinically meaningful benefit in either symptoms, function, or quality of life to better capture the improvements patients experience.⁸ Using the tripartite metric, 69% of VNS Therapy patients achieved clinically meaningful benefit in at least 1 area at 12 months, a statistically significant difference compared with 55% in the sham group.⁸

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Durability stood out. At 24 months, 80% of patients who achieved at least a meaningful benefit (partial response) at 12 months maintained or improved their gains.⁹ Contrast this with medication studies, where relapse rates climb steadily over time.^10,11

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Response rates increased over time. VNS Therapy is not an acute treatment, and it often takes months for the benefits to take effect.⁹ At 12 months, 69% of patients on VNS Therapy had achieved at least a meaningful benefit (partial response) on the CGI-I, but by 24 months that number increased to 77%.⁹ The percent who achieved a substantial benefit (response) on the CGI-I increased from 41% to 52% from months 12 to 24.⁹

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Patients Who Failed ECT or TMS Showed the Greatest Differential Response

Some patients showed particularly strong differential benefit with VNS Therapy compared with sham: those who had previously tried ECT or TMS.¹²

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Patients who had tried ECT (with or without response)—either in their lifetime or during their current episode—showed the largest separation between active and sham VNS Therapy.¹² The same pattern held for patients who had tried TMS (with or without response) during their current episode.¹²

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For patients who have exhausted those options, VNS Therapy offers something genuinely different, not just another iteration of the same approach.

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How VNS Therapy Reaches the Brain

VNS Therapy sends mild, periodic electrical pulses to the left vagus nerve into the nucleus tractus solitarius, which connects to the locus coeruleus (norepinephrine), dorsal raphe nucleus (serotonin), and limbic (dopamine) structures.^13-17 The stimulation is intermittent—typically 30 seconds on, 5 minutes off—creating ongoing modulation rather than continuous activation.¹⁷

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This is fundamentally different from acute interventions like ECT or ketamine. VNS Therapy doesn’t produce rapid response.¹⁷ While the mechanism is unknown, it appears to involve gradual neuroplastic changes and modulation of inflammatory pathways—processes that unfold over months, not days.^18-21

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For clinicians accustomed to seeing medications or ECT work within weeks, VNS Therapy requires recalibrating expectations. The average time to response is 6 to 12 months.¹⁷ Some patients don’t respond until 18 to 24 months of therapy.⁹

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No Cognitive Impairment, No Weight Gain, No Sexual Dysfunction

Dr. Hamish McAllister-Williams made a striking observation: VNS Therapy is “spectacularly well tolerated.” The most commonly reported side effects from stimulation are voice alteration or hoarseness, increased coughing, sore throat, paresthesia, dyspnea, and pain. Infection is the most commonly reported complication of the surgical procedure.

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Side effects typically diminish over time and can be managed by modifying stimulation parameters.^1,17 There’s no cognitive impairment, no weight gain, and no sexual dysfunction.

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For someone who has experienced the cognitive effects of ECT or the side effect burden of multiple medications, this tolerability profile matters.^22,23

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Who Is VNS Therapy Appropriate For?

VNS Therapy is indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.¹⁷

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Based on current evidence, VNS Therapy is most appropriate for:

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• Patients who have been identified as having “difficult-to-treat” depression: “depression that continues to cause significant burden despite usual treatment efforts”⁶
• Patients who are unable to maintain a response or remission to a successful treatment trial²⁴
• Patients who are experiencing continued depression symptoms while undergoing maintenance treatment with ECT, ketamine/esketamine, or TMS and need further add-on treatment²⁴
• Patients who are receiving treatment with high doses of medication and/or experiencing a high side effect burden that may require add-on treatment²⁴
• Patients with a history of ECT or TMS regardless of response¹²

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VNS Therapy is not appropriate as an acute treatment. It is not a replacement for psychotherapy or medications that have not been adequately tried. Chronic or recurrent depression needs more than a quick fix, and VNS Therapy can offer lasting progress that helps patients feel better over time and stay better.¹⁷

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Insurance Coverage Is Evolving

Prior authorization is typically required, and approvals can take time. For practices considering VNS Therapy, thoroughly documenting treatment history is essential. The FDA approval provides a foundation, but individual coverage decisions vary by plan and region.

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TL;DR

The largest and longest clinical trial for VNS Therapy (RECOVER) showed clinically meaningful and significant improvements in measures of symptoms, quality of life, and function despite missing its primary endpoint of percent time in MADRS response. VNS Therapy often takes 6 to 12 months to work, but the benefits tend to persist once achieved. About 80% of patients with at least a meaningful ​benefit (partial response) from VNS Therapy at 12 months maintained this benefit at 18 and 24 months. Patients who had tried ECT or TMS, regardless of response, showed the strongest differential benefit from VNS Therapy.

Tolerability is excellent compared with medications and ECT, and most side effects are stimulation related and decrease over time and/or can be managed with adjustments to stimulation. VNS Therapy is approved for adults with chronic or recurrent depression (major depressive disorder or bipolar disorder) who are experiencing a major depressive episode without adequate response to 4 or more adequate antidepressant treatments.

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Want to learn more about VNS Therapy? Learn More.

This webinar is selected by Osmind to be sponsored by LivaNova, PLC.

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INTENDED USE / INDICATIONS

The VNS Therapy System is indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.

The most commonly reported side effects from stimulation are voice alteration or hoarseness, increased coughing, sore throat, paresthesia, dyspnea, and pain. Infection is the most commonly reported complication of the surgical procedure.

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IMPORTANT SAFETY INFORMATION

https://www.livanova.com/depression/en-us/hcp-safety-information

References

1. Berry SM, et al. Med Devices (Auckl). 2013;6:17-35. 

2. Rush AJ, et al. Biol Psychiatry. 2005;58(5):347-354. 

3. Aaronson ST, et al. Am J Psychiatry. 2017;174(7):640-648. 

4. Conway CR, et al. Brain Stimul. 2025;18(3):676-689.

5. Rush AJ, et al. Brain Stimul. 2025;18(3):690-700.

6. McAllister-Williams RH, et al. J Affect Disord. 2020;267:264-282.

7. Zimmerman M, et al. J Clin Psychiatry. 2012;73(6):790-795. 

8. Conway CR, et al. J Mood Anxiety Disord. 2025;10:100121.

9. Conway CR, et al. Int J Neuropsychopharmacol. 2026;29(1):pyaf080.

10. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917.

11. Rush AJ, et al. Aust N Z J Psychiatry. 2019;53(2):109-118.

12. Aaronson ST, et al. J Clin Psychiatry. 2025;86(3):25m15850.

13. Hachem LD, et al. Neurosurg Focus. 2018;45(3):E2. 

14. Dorr AE, et al. J Pharmacol Exp Ther. 2006;318(2):890-898. 

15. Manta S, et al. J Psychiatry Neurosci. 2009;34(4):272-280. 

16. Manta S, et al. Brain Stimul. 2012;5(3):422-429.

17. Physician’s Manual - VNS Therapy™ Generator and Lead Manual for Depression (US), April 2025.

18. Rosso P, et al. Biomed Rev. 2019;30:99-109. 

19. Biggio F, et al. Int J Neuropsychopharmacol. 2009;12(9):1209-1221. 

20. Meneses G, et al. J Inflamm (Lond). 2016;13:33. 

21. Namgung U, et al. J Neuroinflammation. 2022;19(1):33.

22. Porter RJ, et al. BJPsych Open. 2020;6(3):e40.

23. Cascade E, et al. Psychiatry (Edgmont). 2009;6(2):16-18.

24. Kraus C, et al. Neuromodulation. 2022;25(3):316-326. 


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