What if one of psychiatry's most effective treatments for treatment-resistant depression emerged from watching childbirth breathing techniques?

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About 30% of patients who try two traditional treatments for depression like SSRIs relapse and see no lasting relief. For those who've exhausted every option—medication after medication, therapy combinations, even ECT—psychiatrists face a clinical impasse. But with vagal nerve stimulation (VNS), patients keep getting better, month after month, year after year.

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At Stony Brook University, Dr. Lucian Manu has helped over 20 patients access VNS, many of whom have reduced their reliance on weekly ketamine infusions to monthly or less while maintaining stability. He sat down with Carlene MacMillan, MD, on this episode of Psychiatry Tomorrow.

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What You'll Learn

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• Why VNS emerged from an accidental observation during Lamaze classes and what that tells us about vagal modulation

• How VNS creates a clinical "floor" that prevents patients from reaching their lowest depressive episodes

• The Medicare coverage breakthrough after 15 years of insurance denials—and the cost-effectiveness argument that worked

• Patient selection criteria, practical implementation details, and managing the insurance appeals process

• Why functional improvements often precede symptom score changes

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How Was Vagal Nerve Stimulation Discovered as a Treatment for Depression?

‍The VNS origin story reveals something fundamental about how the vagus nerve modulates mood.

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In the 1980s, neuroscientist Jake Zabara was studying the vagus nerve in dogs when his pregnant wife enrolled in Lamaze breathing classes. Watching her practice regulated breathing techniques, Zabara asked a critical question: How does controlled breathing reduce labor pain?

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His hypothesis centered on the vagus nerve—the largest cranial nerve, with approximately 80% afferent fibers carrying information from internal organs to the brain. He isolated the cervical vagus in dogs and began systematic stimulation. During one experiment, a dog developed seizures. When Zabara stimulated the vagus nerve mid-seizure, the seizure stopped.

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He then induced seizures with strychnine and mapped the precise stimulation parameters needed to abort them. This wasn't just an interesting phenomenon—it revealed that vagal stimulation could powerfully modulate brain activity.

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By 1997, the FDA cleared VNS for refractory epilepsy. But researchers noticed an unexpected pattern: epilepsy patients receiving VNS arrived at monthly follow-ups more engaged, with improved affect. The facility doorman commented that patients "looked better." When surveyed, some reported they had never felt better in their life.

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How Does Vagal Nerve Stimulation Affect the Brain?

PET scans revealed that VNS activates specific regions: the dorsolateral prefrontal cortex, insula, orbitofrontal cortex, and cingulate gyrus—the same structures targeted by TMS for depression.

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The mechanism centers on the vagal pathway to the locus coeruleus. The vagus nerve projects to the solitary tract nucleus, which connects directly to the locus coeruleus—the origin of norepinephrine neurons. When activated, these neurons prime the brain for attention and learning.

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As Dr. Manu explains: "The vagus nerve is like the eyes the brain has turned inward. It collects information from within through afferent fibers. When we stimulate it, we're asking the locus coeruleus to grab attention—to wake up the brain and say, pay attention to this."

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This has implications beyond mood stabilization. Dr. Manu is exploring VNS-assisted psychotherapy, using stimulation to enhance the brain's learning capacity during therapy sessions, similar to ketamine-assisted or psychedelic-assisted approaches.

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What Makes VNS Different from Other Depression Treatments?

By 2005, VNS received FDA approval for treatment-resistant depression. The initial 10-week trial results weren't overwhelming—around 30% response rates. But two features convinced the FDA that VNS warranted approval:

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First, VNS improves over time. Unlike every other psychiatric treatment, which typically shows declining efficacy, VNS patients better at three months were even better at six months. At 12 months, they showed more improvement than at three months. At 24 months, more than 12 months.

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Second, once patients respond, they stay responded. Relapse rates are remarkably low. Once a patient achieves remission with VNS, they're very likely to maintain it—a stark contrast to pharmacotherapy's high relapse rates.

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Dr. Manu uses a vivid metaphor: "It's like acrobats at the circus. When they fall, they have that net. VNS offers a minimum floor; patients who dip no longer go deeper than that floor."

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Does Insurance Cover Vagal Nerve Stimulation for Depression?

Despite FDA approval in 2005, insurance companies refused to cover VNS until 2020, claiming the studies didn't constitute "class one evidence." The device costs $35,000-45,000 upfront (including surgery and device), creating a prohibitive barrier for most patients.

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Eventually, the cost-effectiveness argument won. Prolonged treatment-resistant depression generates substantial costs: ongoing medication trials, frequent ketamine or TMS sessions, psychiatric hospitalizations, emergency department visits, and disability payments. VNS offers a one-time cost that amortizes over years. The battery lasts 5-10 years (typically around 7 years), and follow-up visits are infrequent since the device stimulates continuously.

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In 2020, Medicare reconsidered. They launched the RECOVER trial: a large-scale study at over 80 centers nationwide, primarily enrolling Medicare beneficiaries, to definitively evaluate VNS efficacy and cost-effectiveness in real-world settings.

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How Do You Get Insurance Approval for VNS?

Dr. Manu's experience: "The manufacturer now has a specialized team that helps with single-case agreements for patients who can't enter the trial or choose not to. I've had patients approved after multiple denials and appeals. You have to keep at it—it's a war of attrition—but in most cases, in hindsight, it was worth the effort."

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Which Patients Are Good Candidates for Vagal Nerve Stimulation?

The RECOVER trial inclusion criteria require:

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• Failed at least 4 adequate treatment trials (any modality: medications, psychotherapy, TMS, ECT, ketamine)

• Treatment-resistant depression stable enough to manage the approval timeline

• Realistic expectations about the 3-6 month timeline for effects to emerge

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There's no ceiling on treatment failures. Dr. Manu has implanted patients who've exhausted 20+ interventions.

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Critical clinical consideration: Patients must be stable enough to tolerate the approval process. Those in acute crisis or frequent decompensation aren't good candidates—not because VNS won't work, but because they can't sustain the months-long appeals battle.

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As Dr. Manu notes: "The time to plan for VNS is in times of peace, not under duress in crisis when mood is downswinging."

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What Age Range Benefits from VNS?

Contrary to assumptions about Medicare populations, Dr. Manu's VNS cohort spans ages 30s through 80s, distributed in a bell curve, not skewed toward older patients. Many are on Medicare due to psychiatric disability, not age.

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Does VNS Improve Quality of Life Even When Depression Scores Don't Change Much?

Quality of life and functional improvements often precede (and sometimes exceed) symptom score changes.

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"Even when measurement scales like the MADRS don't show dramatic improvement, patients report enhanced quality of life," Dr. Manu explains. "I've had patients return to part-time or full-time work, improve social functioning, and report subjectively feeling better than they have in years."

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Clinical Pearl: Don't rely solely on self-report scales. Dr. Manu weighs PHQ-9 or other self-report measures against CGI scores, performs a MADRS at least once or twice yearly, and pays close attention to functional markers: return to work, social engagement, reduced utilization of crisis services.

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This quality-of-life-first pattern has implications for how we measure VNS success and when we consider it clinically effective.

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Can VNS Work for Bipolar Depression?

Dr. Manu raises an important diagnostic consideration: "A lot of our 'treatment-resistant unipolar depression' patients may have bipolar depression. There's classic unipolar, classic bipolar, and a whole spectrum in between."

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For these patients, mood fluctuations complicate VNS consideration. During upswings (even mini-upswings), patients feel better and dismiss the need for VNS. During downswings, they're in crisis and can't engage with planning.

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This reinforces the "times of peace" principle: VNS planning requires sufficient stability to make a major treatment decision.

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Can VNS Be Combined with Ketamine or Other Treatments?

One of VNS's most practically valuable features: it pairs exceptionally well with rapid-acting treatments like ketamine.

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"VNS allows patients to rely less on ketamine treatments," Dr. Manu explains. "We can decrease frequency from weekly or every other week to monthly, and sometimes even less frequently."

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VNS provides the floor—the baseline stabilization that prevents deep depressive episodes. Ketamine provides acute relief when patients dip. Over time, as VNS effects build, the floor rises, and patients need less frequent ketamine rescue.

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For clinic capacity: This matters enormously for practices managing high volumes of ketamine patients. Reducing treatment intensity for VNS patients who achieve stability frees appointment slots for new patients or those needing more acute intervention.

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Dr. Manu has also observed VNS synergy with TMS, ECT, and ongoing psychotherapy. VNS creates a foundation that rapid acting treatments to work more effectively.

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What Does the VNS Implantation Procedure Involve?

A common barrier: patients (and some clinicians) overestimate the invasiveness of VNS implantation.

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Dr. Manu's framing: "This is less extreme than ECT. We're dialing up a function that already exists. The vagus nerve modulates mood naturally; we're just asking it to do that more intensely. By the time the battery runs out in seven to nine years, we may have non-invasive alternatives."

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Technical Details

The surgery is outpatient, comparable to pacemaker implantation. A neurosurgeon implants a small pulse generator in the left chest wall with a lead wire wrapped around the left cervical vagus nerve. The device delivers intermittent stimulation 24/7, typically cycling on for 30 seconds, off for several minutes.

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Parameters can be adjusted non-invasively at follow-up visits using an external programmer, similar to programming a pacemaker.

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Side effects are minimal. Most common: mild hoarseness or voice change during stimulation cycles, which patients typically habituate to. In Dr. Manu's 21 implanted patients, none have requested device removal.

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Battery life: 5-10 years, typically around 7 years. Replacement requires a minor outpatient procedure to swap the chest unit; the vagal lead remains in place.

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How Should Psychiatrists Introduce VNS to Patients?

Dr. Manu's method: "When I see a new patient who's a candidate for interventional treatments, I go through the gamut in our second session. I compare and contrast all options: ketamine, TMS, ECT, VNS. I plant that seed early."

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Why this works:

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• Patients develop "transference" toward different modalities

• Starting with preferred treatments builds alliance

• When those treatments plateau, VNS becomes a natural next step rather than a desperate last resort

• Patients who've heard about VNS from the beginning are less resistant when it becomes clinically appropriate

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What to emphasize:

• VNS is less unnatural than ECT. We're enhancing an existing mood-regulation function

• The "acrobat's net" metaphor: preventing falls to the lowest depths

• Improvement-over-time pattern unique to VNS

• Reduced reliance on frequent office visits for ketamine/TMS once stabilized

• Return-to-function outcomes even when symptom scores are modest

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What not to say: Avoid overselling. Dr. Manu recalls patients who "barged in asking for VNS," and he deliberately temporized their enthusiasm. "I put them on hold, evaluated carefully, tried to curb their enthusiasm. One ended up implanted and was lost to follow-up—not sure what happened there."

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When Should Psychiatrists Consider VNS for Treatment-Resistant Depression?

Dr. Manu describes a typical scenario: "When you're at the point where there's nowhere else to go, VNS is invaluable. It buys you time. As you pursue VNS, you give the patient hope, a light at the end of the tunnel. That's the unintended byproduct of VNS: it provides psychological sustenance during what can be a months-long approval process."

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For patients who've cycled through every evidence-based intervention, VNS offers a mechanism-based alternative that addresses the problem from a different angle.

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Is There a Non-Invasive Alternative to Implanted VNS?

Transcutaneous auricular VNS (ta-VNS)—stimulation through the external ear—is showing promise in research. Critics argue the "bandwidth" is smaller than cervical VNS, but imaging studies suggest comparable brain activation patterns.

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Dr. Manu is exploring whether ta-VNS could serve as a gateway: "Patients could try the non-invasive version. If it's working but cumbersome, they could transition to cervical implantation—set it and forget it."

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He's also investigating respiratory-gated VNS (stimulation synchronized with breathing cycles) and sleep-cycle-modulated stimulation in collaboration with researchers studying delirium in trauma surgery ICU patients.

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The broader vision: VNS-assisted psychotherapy, using stimulation to prime the brain's attention and learning systems before therapy sessions, potentially creating more durable therapeutic gains.

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Other Frequently Asked Questions About VNS for Depression

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How long does VNS take to start working for depression?

VNS effects typically emerge over 3-6 months, which is slower than ECT (1-2 weeks) or ketamine (hours to days) but faster than most medication adjustments. The key difference: VNS continues improving at 12 and 24 months rather than plateauing or declining. This delayed onset means patient selection should prioritize stability over urgency—those in acute crisis or with active suicidality need faster-acting interventions like ECT or ketamine. The progressive improvement pattern also means early response at 3 months predicts even better outcomes at 6-12 months, unlike most treatments where early response represents peak efficacy.

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What are the side effects of vagal nerve stimulation?

The most common side effect is mild hoarseness or voice changes during the 30-second stimulation cycles, which most patients habituate to over time. In Dr. Manu's experience with 21 implanted patients at Stony Brook University, none have requested device removal due to side effects, an exceptionally low explantation rate.

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How much does VNS cost for depression treatment?

VNS costs $35,000-45,000 upfront, including the device, surgical implantation, and initial programming. However, this one-time cost amortizes over 5-10 years (typical battery life: 7 years) and can be more cost-effective than ongoing weekly ketamine infusions, repeated TMS courses, psychiatric hospitalizations, and disability payments associated with prolonged treatment-resistant depression.

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Does Medicare cover VNS for treatment-resistant depression?

Yes. After refusing coverage from 2005-2020, Medicare launched the RECOVER trial in 2020—a large-scale effectiveness study at over 80 centers nationwide. Most participants are Medicare beneficiaries, including many younger patients on Medicare due to psychiatric disability rather than age. For non-Medicare patients, LivaNova offers assistance with single-case insurance agreements.

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Can patients feel the VNS device stimulating?

Patients typically feel mild sensations during stimulation cycles, most commonly slight hoarseness or voice changes when the device activates for 30 seconds every few minutes. These sensations usually diminish as patients habituate. The device operates continuously 24/7 with programmable on/off cycles, similar to a pacemaker's constant function.

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How often do VNS patients need follow-up appointments?

VNS requires infrequent follow-up visits compared to weekly ketamine infusions or daily TMS sessions. After initial programming and titration, patients may need appointments every few months to adjust stimulation parameters using an external programmer. The device operates continuously without requiring patient intervention.

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Can VNS replace my patient's ketamine or other depression treatments?

VNS doesn't replace other treatments; it creates a foundation that enhances their effectiveness. The typical pattern: patients continue medications and therapy while gradually reducing neuromodulation frequency. For ketamine specifically, patients often decrease from weekly infusions to biweekly, then monthly, as VNS effects build over 6-12 months. Some patients eventually discontinue ketamine entirely while maintaining stability, but this should be gradual and monitored closely using functional markers (work performance, social engagement) alongside symptom scales. The clinical model works because VNS provides the "floor" (baseline stabilization) while ketamine addresses acute dips—as the floor rises over time, rescue interventions become less frequent.

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What's the success rate for VNS in treatment-resistant depression?

Initial FDA approval trials showed approximately 30% response rates at 10 weeks, which is modest compared to other treatments. However, VNS's unique feature is progressive improvement: response rates increase over time rather than declining. By 12 months, significantly more patients respond than at 3 months, and by 24 months, even more than at 12 months. This inverted trajectory means VNS "success" should be measured at 12+ months, not 10 weeks. Additionally, once patients achieve response or remission, relapse rates are remarkably low compared to pharmacotherapy. The distinction matters: VNS may not get the most patients to remission fastest, but it keeps responders well longer than any other intervention.

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Is VNS more invasive than ECT?

VNS involves one-time surgical implantation comparable to pacemaker surgery, while ECT requires repeated anesthesia and treatments over weeks. As Dr. Manu explains, VNS is "less unnatural than ECT" because it enhances an existing mood-regulation function of the vagus nerve rather than inducing seizures. From a patient perception standpoint, many find the one-time surgical procedure less daunting than repeated anesthesia, though others prefer ECT's faster onset and non-surgical approach. The choice depends on urgency (ECT works in 1-2 weeks vs. VNS taking 3-6 months), previous treatment response, patient anxiety about surgery versus anesthesia, and whether maintenance treatment burden matters (VNS requires minimal follow-up after implantation; ECT often requires ongoing maintenance sessions).

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How is the VNS device implanted?

A neurosurgeon performs outpatient surgery comparable to pacemaker implantation. The procedure involves implanting a small pulse generator in the left chest wall with a lead wire wrapped around the left cervical vagus nerve. The surgery takes a few hours, and most patients return home the same day. Parameters can be adjusted non-invasively at follow-up visits.

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What is transcutaneous auricular VNS (ta-VNS)?

Transcutaneous auricular VNS (ta-VNS) stimulates the vagus nerve through the external ear without surgery. While the "bandwidth" is smaller than cervical VNS, imaging studies show comparable brain activation patterns. Ta-VNS may serve as a gateway—patients could trial the non-invasive version and transition to implantation if it works but feels cumbersome. Research is ongoing into respiratory-gated and sleep-cycle-modulated non-invasive VNS.

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Can patients with VNS devices have MRI scans?

Most modern VNS devices are MRI-conditional, meaning MRI scans are possible under specific conditions and with certain precautions. Patients should inform all healthcare providers about the VNS device, especially before imaging procedures. The device manufacturer (LivaNova) provides detailed MRI safety guidelines, and the device can be temporarily turned off if needed.

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Who should I contact to refer a patient for VNS?

Contact LivaNova for the nearest RECOVER trial site or single-case agreement support. In the tri-state New York area, Dr. Lucian Manu at Stony Brook University serves as a liaison and welcomes inquiries about patient selection and referral coordination. Most academic medical centers with epilepsy programs have neurosurgeons experienced with VNS implantation.

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Does VNS work for bipolar depression or just unipolar depression?

Many patients diagnosed with "treatment-resistant unipolar depression" may have unrecognized bipolar depression along a spectrum. VNS has been studied primarily in treatment-resistant depression regardless of bipolar subtype. However, mood stability is important for managing the approval process; patients need sufficient stability during upswings and downswings to sustain the months-long insurance appeals and planning process.

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How long does the VNS battery last?

The VNS device battery typically lasts 5-10 years, with an average of approximately 7 years. Battery replacement requires a minor outpatient procedure to swap the chest unit; the vagal nerve electrode remains in place and doesn't need to be repositioned.

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TL;DR: Key Takeaways for VNS in Clinical Practice

Vagal nerve stimulation offers a mechanistically distinct option for treatment-resistant depression with two unprecedented features: effects that improve over time (rather than decay) and remarkably low relapse rates once response is achieved.

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Clinical advantages:

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• Creates a "floor" preventing patients from reaching deepest depressive episodes

• Reduces reliance on frequent ketamine infusions (weekly → monthly or less)

• Functional improvements often precede symptom score changes

• Extremely low device removal rates

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Practical implementation:

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• Ideal candidates: failed 4+ adequate treatment trials, stable enough to manage approval process

• Medicare now covering through RECOVER trial at 80+ sites nationwide

• Manufacturer assistance available for single-case insurance appeals

• Procedure comparable to pacemaker implantation; battery lasts 5-10 years

• Present VNS early in treatment planning rather than as desperate last resort

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Access: Contact Livanova for nearest RECOVER trial site or single-case agreement support. Dr. Manu serves as a liaison for the tri-state New York area and welcomes inquiries about patient selection and referral coordination.

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For patients who've exhausted conventional options, VNS represents a fundamentally different approach to creating sustainable mood stabilization.

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Timestamped Show Notes

[00:00:00] Introduction: VNS as a treatment discovered by accident

[00:01:00] Dr. Will Sauvé joins as new co-host

[00:02:00] Why VNS is gaining momentum now

[00:03:00] Dr. Manu's journey into VNS starting in 2016

[00:05:00] The vagus nerve: anatomy and function—80% afferent, pathway to locus coeruleus

[00:08:00] Jake Zabara's serendipitous discovery at Lamaze class

[00:11:00] From stopping dog seizures to human epilepsy treatment

[00:13:00] PET scans reveal VNS targets same brain regions as TMS; patients report feeling better than ever

[00:16:00] The two unique features that convinced the FDA: improvement over time, low relapse

[00:19:00] Why insurance companies refused coverage 2005-2020: not "class one evidence"

[00:22:00] The RECOVER trial and Medicare breakthrough—cost-effectiveness argument

[00:27:00] Getting single-case agreements through appeals: "war of attrition"

[00:31:00] Patient selection criteria: 4+ failed treatments, bell curve age distribution, no ceiling on failures

[00:34:00] Comparing VNS to ECT: "less extreme, more natural—dialing up existing function"

[00:35:00] Bipolar depression often underdiagnosed in "treatment-resistant" populations

[00:38:00] How VNS reduces ketamine treatment frequency: creating the floor while ketamine provides acute relief

[00:42:00] The surgical procedure: outpatient, comparable to pacemaker, 21 patients with zero explantation requests

[00:46:00] Quality of life improvements precede symptom scores; using MADRS and CGI to counter self-report bias

[00:50:00] Transcutaneous auricular VNS: the non-invasive future, respiratory-gated stimulation research

[00:53:00] VNS-assisted psychotherapy: priming the brain to learn by activating locus coeruleus attention systems

[00:56:00] Trauma surgery ICU delirium study with ta-VNS—cross-disciplinary collaboration