Vagus nerve stimulation (VNS) has been shown to be effective as an adjunct treatment for treatment-resistant depression (TRD). VNS leads to antidepressive and antisuicidal effects and quality of life improvements. This protocol offers a step-by-step guide to managing and adjusting a vagus nerve stimulator for efficient treatment of TRD.
Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression (TRD). VNS exhibits antidepressive and stabilizing effects. This method is particularly useful as a long-term treatment, in which up to two-thirds of patients respond. The vagus nerve stimulator is positioned on the left vagus nerve during a surgical procedure and is activated telemetrically by a wand connected to a handheld computerized device. The treating physician can perform various adjustments of the vagus nerve stimulator during in-office visits (e.g., by modifying stimulation intensity or stimulation frequency) to achieve maximum therapeutic effects with low side effects. Set-up of the device usually takes several months. Typical side effects include wound infection, temporary salivation, coughing, paralysis of the vocal cords, bradycardia, or even asystole. The patient can stop the VNS by placing a magnet over the generator. The current protocol describes delivery of the specific stimulation tool and methods for adjusting the tuning parameters to achieve the best remission rates in patients with TRD.
Major depressive disease (MDD) is a frequently recurring or chronic psychiatric disease with high prevalence1,2 and is characterized by alterations in affect and mood. Of utmost importance is the association of MDD with high rates of suicidality and mortality3,4,5,6. Pharmacological treatment strategies include monoamine neurotransmitter reuptake inhibition [e.g., treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)], lithium augmentation, or atypical antipsychotic augmentation strategies7,8. In addition to pharmacological treatment, psychotherapeutic approaches and supplemental noninvasive strategies are used to treat MDD8,9,10. Alternative strategies such as light-based therapy, exercise, acupuncture, and yoga have also been successfully used in treatment of MDD8,9,11,12; although, these are not approved methods. However, up to 30–50% of all patients with MDD do not achieve remission with currently available treatment options13. This subtype of MDD is called therapy-resistant depression (TRD)14,15,16. TRD is defined as the failure of two successive trials of antidepressant treatment administered at an appropriate dose and for a sufficient duration17,18,19.
The high rate of TRD poses a challenge in the overall management of patients with MDD13; thus, innovative add-on therapies for TRD are urgently needed. Neurostimulation tools such as electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), magnetic seizure therapy (MST), cranial electrotherapy (CES), and vagus nerve stimulation (VNS) are clinically available and promising tools in the psychiatric armamentarium for patients with TRD20. VNS is particularly useful in TRD and exhibits antidepressant and mood stabilizing effects. During long-term treatment (>12 months), up to two-thirds of patients have responded favorably21,22,23. The American Psychiatric Association recommends the use of VNS as a treatment option after four treatment failures22.
In this study, we outline a protocol for clinicians, describing how to use and set up the VNS instrument for the continuous treatment of TRD. Additional notes on hardware components are included to help readers choose the product that best suits a patient's needs.
VNS is a neurostimulation tool for chronic depression and TRD in patients aged 18 years or older who do not respond to other antidepressant treatments. VNS has been approved for use in the European Union and the United States22. VNS has been shown to be effective as an adjunctive treatment in TRD22; moreover, it has antisuicidal effects and improves quality of life22.
In this article, we present a protocol and additional information to help clinicians properly implement VNS in patients with TRD. The treating psychiatrist is responsible for the optimal dosing of the vagus nerve stimulator and for considering all aspects of the therapy, including the safety, tolerability, and efficacy of VNS in patients with TRD.
VNS requires an implantable pulse generator, which is surgically inserted under the skin of the chest, as described in the protocol. The VNS therapy pulse generator for depression treatment is placed subcutaneously in the left chest wall. Standard wound care is recommended during the first week after the procedure34,35. The repeated stimulation of the vagus nerve sends impulses from the peripheral nervous system, where the electrode is placed to the brain. The negative electrode generates action potentials that travel afferently via sensory fibers, while efferently traveling action potentials are mostly blocked by the positive electrode. Unblocked action potentials can cause side effects. A distance of approximately eight millimeters between the negative and positive electrodes is recommended36.
It is suggested not to use the right vagus nerve because of the risk of severe bradycardia and arrhythmias. In contrast, no such side effects have been reported when the left vagus nerve was used; however, several patients have had right-sided implants with good results. Surgical implantation is performed by means of minor surgery (mainly neurosurgical)37,38. The most frequent acute complications of vagus nerve stimulator implantation include temporary salivation, coughing, paralysis of the vocal cords, and lower facial weakness. Bradycardia occurs rarely, and asystole occurs very rarely. The risk for infection at the VNS site can be approximated to be between 1.1 and 3.9%36.
Regarding psychiatric adverse effects, the rate of stimulation-induced switch to mania or hypomania in the VNS trials was low (i.e., <0.01% at one year), and those symptoms diminished after modifying the stimulation parameters29. Side effects are generally fully reversible37,39. Adverse events reported during the first and second years on VNS therapy are summarized in Table 133.
During surgery, the vagus nerve stimulator is regularly switched on to 0.5 mA to check whether the device is working properly and to avoid side effects such as asystole. After functionality has been verified, the device is switched off again. At least two weeks (depending on the potential side effects of tuning the VNS) after the device has been implanted, the vagus nerve stimulator is switched on again. Normal-mode stimulation is applied 24 h per day.
The stimulation amplitude is optimized with respect to the therapeutic effect and/or tolerability. The device is activated telemetrically by a wand connected to a handheld computerized device during psychiatric in-office visits. In general, the dose (i.e., the amplitude) is set to a level that the patient can tolerate (see Table 2). Adjustment of the treatment parameters, including output current, signal frequency, pulse width, signal on time, and signal off time, is non-invasively performed using the external interface. Importantly, the patient can stop the VNS stimulation by placing a magnet over the generator. After the magnet is removed, the generator restarts in normal-mode stimulation. The normal-mode output current can be increased to a therapeutic range as quickly as tolerable. More frequent visits (approximately 1 to 2 visits per week) at the beginning of the stimulation are recommended. Usually, stimulation is increased by 0.25 mA per visit. However, multiple 0.25 mA increases may be made at a single visit to reach the therapeutic range more quickly. Nevertheless, it is essential to ensure patient tolerance before making additional adjustments. The therapeutic range is usually between 1.0 and 2.0 mA. In some patients, it is necessary to use higher output currents to receive additional efficacy. The effect of VNS is based on distinct mechanisms and is related to the anatomy of the vagus nerve.
The vagus nerve has anatomical connections, including those to the nucleus tractus solitaries, locus coeruleus, raphe nuclei, amygdala, hypothalamus, and orbitofrontal cortex40. VNS can increase the metabolic activity in the main serotonin- and noradrenalin-producing nuclei, resulting in augmented neurotransmitter concentrations in the CSF41,42. Thus, the mode of action of VNS works analogously to most antidepressants.
Neuroimaging studies have shown that activity in the thalamus and cortex of depressed patients is changed by VNS therapy. Changed activity in the orbital and ventromedial prefrontal cortices has also been recorded43,44. Several imaging studies have suggested that VNS therapy is associated with decreased metabolic activity in the right hemisphere and increased metabolic activity in the left hemisphere, thus attenuating the hemispheric imbalance in depressive patients40,45,46,47. Vagal afferents express IL-1β receptors that convey inflammatory signals to the hypothalamus, leading to a release of hypophysis adreno-corticotrophin hormones. This pathway also stimulates glucocorticoid release by the adrenal glands via a decrease in peripheral inflammation processes. In the vaso-vagal-inflammatory reflex loop, vagal afferents activate vagal efferents, which release acetylcholine (ACh) at the distal end of the vagus nerve, inhibiting the release of pro-inflammatory cytokines such as TNFα48. In summary, the short- and medium-term antidepressant effects of VNS may be related to the increased availability of serotonin and noradrenalin, similar to the mechanism of antidepressive medication49. Long-term VNS has different effects than short-term VNS. The long-term antidepressant effects of VNS may be related to mitigation of the interhemispheric imbalance associated with depression (i.e., right-sided inhibition and left-sided activation)45. Moreover, VNS may reduce inflammation that contributes to depression50, though not all the mechanisms of action of VNS are completely understood yet. The effects are thought to be gradual and acting with latency; consequently, VNS is usually not indicated for the relief of acute depressive symptoms32.
Up to 60% of patients with TRD show reduction in their depressive symptoms22,23,49,51,52. Long-term follow-ups also indicate fewer suicide attempts and lower levels of suicidal ideations and thoughts. Also documented are fewer hospitalizations in patients treated with VNS in addition to pharmacotherapy compared to patients with the same level of depression symptom severity who were only taking medications22,29,53.
Antidepressant and relapse prevention effects can even be observed after a long-term follow-up of 5 years22,23. Recently, in a large sample of patients with TRD, Aaronson and colleagues have shown significantly higher 5 year cumulative response rates and significantly higher remission rates in patients treated with VNS compared to patients who were only TAU22. The best-responding group consisted of patients with a history of good responses to ECT before receiving VNS22. The number needed to treat (NNT) for VNS ranges from 4 to 10. Given the high level of treatment resistance in this population of patients, the NNT remains clinically significant32.
Therefore, the long-term results of VNS are distinctly promising, suggesting that VNS might be particularly useful for patients with chronic depression for whom treatment resistance is a challenge20. Thus, after approximately 3 to 6 months of VNS therapy, treatment results can be expected.
The common definition of TRD is treatment failure of at least two antidepressants17,18,19. However, most patients with TRD who are treated with VNS have undergone more than two treatment trials of antidepressant medication before device implantation22. For example, in the longitudinal study by Aaranson et al. (2017)22, patients who were treated with VNS failed an average of 8 treatments. The findings suggest that VNS might also be particularly useful in much heavier states of TRD. Antidepressive VNS therapy is mostly based on modifications to the output current and signal frequency. Changing the settings of on/off time parameters usually leads to a reduction in side effects.
Similar to TRD, VNS has been evaluated for its possible use for other psychiatric diseases, such as bipolar major depressive disorder, Alzheimer's disease, schizophrenia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, treatment-resistant rapid-cycling bipolar disorder, fibromyalgia, and Prader-Willi syndrome54. The efficacy of VNS for affective disorders has been clearly demonstrated20,22,23,54; however, for other psychiatric conditions, there have not yet been reports of either no effect or only preliminary data on efficacy54. Thus, no final conclusion about the efficacy of VNS in these psychiatric indications can be made currently. However, there may be potential for future therapeutic approaches54. Moreover, VNS is not only in the psychiatric armamentarium, as it is a common treatment method for treatment-refractory epilepsy55. In epilepsy patients, the stimulation parameters of the vagus nerve stimulator are similar to the settings in patients with TRD.
Initially, mood improvement in epilepsy patients with VNS led to the conclusion that VNS might also be useful in affective disorders32. VNS has also been assessed for the treatment of tinnitus56, inflammatory bowel diseases57, heart failure58, rheumatoid arthritis59, and many other conditions. Although preliminary data are promising, future evaluations are necessary for understanding the possible mechanisms and therapeutic potential in various clinical conditions and diseases.
Nevertheless, approximately one-third of patients with TRD do not adequately respond to VNS23. Moreover, the abovementioned side effects of VNS can limit its therapeutic action32. However, in cases of insufficient response or intolerable side effects, clinicians can modify the setup of the vagus nerve stimulator. Fine-tuning of the vagus nerve stimulator offers various possibilities for generating desirable responses to different medical conditions. Future perspectives to improve VNS efficacy and reduce side effects, such as including increasing the battery life, shortening the response time, transcutaneous stimulation, and identification of prognostic factors for valuable responses, should be further investigated.
The authors have nothing to disclose.
This study was financially supported by LivaNova, Inc.
VNS Therapy AspireSR Model 106 Generator | LivaNova Inc. | Primary DI Number: 05425025750061 | Implantable Pulse Generator |
VNS Therapy Programming Wand Model 2000 | LivaNova Inc. | Primary DI Number: 05425025750177 | Programming Wand |
VNS Therapy Demipulse Model 103 Generator | LivaNova Inc. | Primary DI Number: 05425025750030 | Implantable Pulse Generator |
Cyberonics Tunneler Model 402 | LivaNova Inc. | Primary DI Number: 05425025750238 | Tunneler |
VNS Therapy Model 502 Accessory Pack | LivaNova Inc. | Primary DI Number: 05425025750245 | VNS Therapy Accessory Pack |
VNS Therapy Model 302 Lead | LivaNova Inc. | Primary DI Number: 05425025750108 | Implantable Bipolar Lead |
Propofol | Merck | CAS Number: 2078-54-8 | [(CH3)2CH]2C6H3OH |
Remifentanyl | Merck | CAS Number: 132539-07-2 | C20H28N2O5 · HCl |
Rocoronium bromide | Merck | CAS Number: 119302-91-9 | C32H53BrN2O4 |