VNS for Bipolar Depression

(RECOVER Trial)

Recruiting at 59 trial locations

Overseen By Mary L Stedman, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: LivaNova

Disqualifiers: Psychotic disorders, Schizophrenia, Bipolar, Dementia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

6800 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called VNS Therapy®, which uses mild electrical pulses to stimulate the vagus nerve. Researchers aim to determine if this treatment reduces depression symptoms more effectively than no stimulation. The trial includes two groups: one receives active stimulation, while the other has the device implanted but not activated for the first year. It suits individuals who have experienced major depression for at least two years or have had at least four depressive episodes without relief from other treatments. Participants must maintain a stable medication routine before joining. As an unphased trial, this study allows participants to contribute to innovative research that could lead to new treatment options for depression.

Will I have to stop taking my current medications?

The trial requires that you maintain a stable medication regimen for at least four weeks before the device is implanted, so you should not stop taking your current medications.

What prior data suggests that VNS Therapy is safe for treating depression?

Research has shown that Vagus Nerve Stimulation (VNS) is safe for individuals with depression unresponsive to other treatments. Studies indicate that most patients tolerate VNS well, experiencing few serious side effects.

One study found that patients using VNS had better outcomes than those who did not, suggesting the treatment's effectiveness and safety. Additionally, the FDA has approved VNS for treatment-resistant depression, confirming its safety.

Overall, the evidence on VNS is positive, indicating it as a safe option for those dealing with difficult-to-treat depression. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for depression, like antidepressant medications and psychotherapy, focus on altering brain chemistry or addressing psychological factors. However, Vagus Nerve Stimulation (VNS) Therapy® is unique because it directly targets the vagus nerve, which plays a crucial role in regulating mood and emotional well-being. By stimulating this nerve, VNS Therapy® has the potential to offer relief for individuals who haven't responded to traditional treatments. Researchers are excited about this approach because it taps into a novel pathway for mood regulation, offering hope for more effective management of depression.

What evidence suggests that VNS Therapy could be effective for depression?

Research has shown that stimulating the vagus nerve (VNS) can help reduce depression symptoms, especially in individuals who haven't responded to other treatments. In one study, about 29% of participants improved after a year of VNS therapy. Another study found that those who didn't respond well to antidepressants experienced the best results with VNS. In this trial, participants in the active arm will have VNS activated two weeks post-implant, while the control group will have the device implanted but not activated for the first 12 months. A major study demonstrated that VNS was more effective in improving depression symptoms than a placebo (inactive) treatment. Overall, VNS appears promising for treating depression, particularly in hard-to-treat cases. ^{3 4 6 7 8}

Who Is on the Research Team?

Charles Conway, MD

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults with treatment-resistant depression, which means they've tried at least four different treatments without success. They should be currently in a major depressive episode that's lasted for two years or more, or have had at least four episodes of major depression. Participants must not change their medications for four weeks before getting the VNS device and can't join if they have certain cognitive disorders, a history of rapid cycling bipolar disorder, schizophrenia, other psychotic disorders, or current suicidal thoughts.

Inclusion Criteria

Patients must maintain a stable medication regimen for at least four weeks before device implantation.

The patient's depressive illness meets a minimum criterion of four prior failed treatments of adequate dose and duration as measured by a tool designed for this purpose.

I have been diagnosed with major depression twice in the last 45 days.

Exclusion Criteria

I have never had rapid cycling bipolar disorder.

I am not currently participating in another clinical trial for drugs or devices.

You have been diagnosed with schizophrenia or schizoaffective disorder at any point in your life.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Implantation

Participants are implanted with the VNS Therapy device

2 weeks

Treatment

Active VNS Therapy treatment or no stimulation control for 12 months

12 months

Open-label extension

All subjects transition to open-label VNS Therapy, including control group activation

5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• VNS Therapy® System

Trial Overview The study is testing whether using Vagus Nerve Stimulation (VNS) as an additional treatment helps reduce symptoms of severe depression compared to no stimulation control after one year. Patients are randomly assigned to either receive active VNS Therapy or be part of the control group that does not receive stimulation.

How Is the Trial Designed?

Group I: Active Active Control 1 Intervention

Group will have VNS activated 2 weeks post implant.

Group II: Control Placebo Group 1 Intervention

Group will be implanted with VNS but device is not activated for the first 12 months. After 12 months, this group can receive stimulation.

Who Is Running the Clinical Trial?

LivaNova

Lead Sponsor

Trials

66

Recruited

31,100+

Vladimir A. Makatsaria

LivaNova

Chief Executive Officer since 2024

Bachelor of Arts in Physiology, Master of Healthcare Administration, and Master of Business Administration from the University of Minnesota

Dr. Deanna Wilke

LivaNova

Chief Medical Officer since 2023

MD from Harvard Medical School

Published Research Related to This Trial

Vagus Nerve Stimulation (VNS) has shown promising long-term antidepressant effects when combined with standard treatment in over 1100 patients with difficult-to-treat depression, particularly after 12 months of stimulation.

A recent randomized trial did not show immediate benefits from VNS, suggesting that longer treatment durations are necessary to fully assess its efficacy and that new metrics are needed to evaluate clinically meaningful improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders. Sackeim, HA., Dibué, M., Bunker, MT., et al.[2022]

Vagus Nerve Stimulation (VNS) has been used since the 1990s as an effective treatment for epilepsy, and emerging data suggest it may also be beneficial for treatment-resistant depression due to its connections to brain areas that regulate mood.

PET studies indicate that VNS induces functional changes in brain regions associated with affect, providing insight into its potential mechanisms of action as an antidepressant, although further research is needed to confirm its efficacy and specific uses in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vagus nerve stimulation. A potential therapy for chronic/recurrent depression?]. Rush, AJ., Linden, M., Zobel, A.[2006]

Vagus nerve stimulation (VNS) therapy is FDA-approved for treatment-resistant depression in adults and has shown long-term antidepressant effects based on clinical studies.

The paper also explores the potential use of VNS therapy for treatment-resistant depression in adolescents and children, indicating its broader applicability beyond just adult patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation: can it be used in adolescents or children with treatment-resistant depression? Yu, ZJ., Weller, RA., Sandidge, K., et al.[2021]

Vagus nerve stimulation (VNS) is being explored as a treatment for major depression that does not respond to traditional medications, although its exact mechanism of action is still unclear.

This review examines preclinical studies of VNS in relation to two key theories of depression: the monoaminergic hypothesis, which focuses on neurotransmitters, and the neural plasticity hypothesis, which emphasizes the brain's ability to adapt and change.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antidepressant mechanism of action of vagus nerve stimulation: Evidence from preclinical studies. Grimonprez, A., Raedt, R., Baeken, C., et al.[2021]

In a retrospective study of 62 patients treated with vagus nerve stimulation (VNS) for epilepsy, only 6 patients experienced significant seizure reduction, indicating that while VNS can be beneficial, it may not be effective for the majority of patients.

Contrary to its reputation for low adverse effects, the study found that only 9 patients had no adverse effects, with some experiencing severe and even life-threatening complications, highlighting the need for careful monitoring throughout the treatment process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vagus nerve stimulation therapy in epilepsy patients: long-term outcome and adverse effects: a retrospective analysis]. Carius, A., Wintermantel, A.[2022]

In a study of 15 patients with treatment-resistant depression, vagus nerve stimulation (VNS) significantly reduced depression scores over 12 months, with a mean Beck Depression Inventory score dropping from 37.8 to 24.6, indicating a positive treatment effect.

By the end of the year, 28.6% of patients showed a response to VNS, and 7.1% achieved remission, with side effects like hoarseness and nausea being common but not leading to treatment discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. Cristancho, P., Cristancho, MA., Baltuch, GH., et al.[2012]

Vagus nerve stimulation (VNS) is a promising treatment for intractable epilepsy and severe depression, providing a reliable option for patients who do not respond to traditional therapies, with mild to moderate side effects that can often be managed by adjusting the device.

Approximately 50% of epilepsy patients achieve satisfactory treatment with monotherapy, and this rate increases to 75% with polytherapy; however, about one-third of patients remain refractory to all treatments, highlighting the need for alternative approaches like VNS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation. Ekmekçi, H., Kaptan, H.[2020]

Vagus nerve stimulation (VNS) is a promising device-based therapy for treatment-resistant depression, which is a significant issue affecting both healthcare costs and patient well-being.

Understanding the initiation, implantation, and monitoring of VNS treatment is crucial for psychiatric nurses to improve care for patients suffering from this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for severe depression. Rado, J., Janicak, PG.[2019]

Vagus nerve stimulation (VNS) is an effective treatment for major depressive episodes, showing a symptomatic response in 15-17% of patients after 10 weeks and 22-37% after 12 months, with remission rates of 15-17% after a year.

VNS is well-tolerated with high continuation rates (90-98%) and low adverse event-related discontinuations (3%), and it does not produce systemic side effects like traditional antidepressants, making it a safe alternative for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation for Major Depressive Episodes. Eljamel, S.[2015]

A systematic review of 14 studies found that vagus nerve stimulation (VNS) showed a significant reduction in depression scores and a 31.8% response rate in uncontrolled studies, indicating potential efficacy.

However, a randomized control trial with 235 patients found no significant difference between VNS and placebo, suggesting that the positive results in earlier studies may be influenced by a placebo effect rather than true therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Martin, JL., Martín-Sánchez, E.[2022]

In a study of 11 patients with chronic treatment-resistant depression, vagus nerve stimulation therapy led to significant reductions in depression scores over one year, with response and remission rates of 55% and 27%, respectively.

While the therapy showed promise in improving mood, it was associated with common and sometimes severe side effects, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in chronic treatment-resistant depression: preliminary findings of an open-label study. Corcoran, CD., Thomas, P., Phillips, J., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11682255/

Vagus nerve stimulation (VNS) for treatment-resistant ... VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21295002/

Effectiveness and safety of vagus nerve stimulation for ... By 1 year, 28.6% (n = 4) of the sample responded to VNS and 7.1% (n = 1) remitted according to the BDI. Secondary outcomes on the Hamilton Depression Rating ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0165032725004720

Characterizing the effects of vagus nerve stimulation on ... A randomized sham-control trial of adjunctive VNS was conducted in 493 participants with markedly treatment-resistant MDD.

4. med.uth.edu med.uth.edu/psychiatry/2025/02/24/key-insights-from-a-landmark-study-exploring-vagus-nerve-stimulation-for-treatment-resistant-depression/

Key Insights from a Landmark Study Exploring Vagus Nerve ... 1. Efficacy Results · Clinician-rated Clinical Global Impression–improvement (CGI-I) showed a higher response rate with active VNS (P = 0.004).

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.2017.16010034

A 5-Year Observational Study of Patients With Treatment ... A diagnosis of severe recurrent major depressive disorder was reported in 46% of patients in the VNS arm and 32% of patients in the treatment-as ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2990624/

Vagus Nerve Stimulation (VNS) and Treatment of Depression This review of VNS will assess the efficacy and safety data that led to the FDA approval. We will also review for the busy clinician how VNS is likely to ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032725019251

Long-term efficacy and safety of vagus nerve stimulation in ... Vagus Nerve Stimulation (VNS) is an approved neuromodulation treatment for individuals with Treatment-Resistant Depression (TRD).

8. brainstimjrnl.com brainstimjrnl.com/article/S1935-861X(24)01390-1/fulltext

Vagus nerve stimulation in treatment-resistant depression: ... VNS was found safe and effective in participants with marked TRD. Keywords. Treatment-resistant depression · Vagus nerve stimulation · Adjunctive therapy ...