Vagus Nerve Stimulation: A New Tool for Treating Depression

Lauren B. Marangell, MD, Melisa Martinez, MD, James M. Martinez, Mark S. George, MD, and Harold A. Sackeim, PhD

Dr. Marangell is Brown Foundation Chair of the Psychopharmacology of Mood Disorders department, Dr. M. Martinez is an instructor with the Mood Disorders Center, and Dr. J.M. Martinez is assistant professor of psychiatry, treating psychiatrist, and assistant director of the Mood Disorders Program, all at Baylor College of Medicine in Houston, Texas.

Dr. George is on staff in the Department of Psychiatry at the Medical University of South Carolina in Charleston.

Dr. Sackeim is chief of the Department of Biological Psychiatry and professor of clinical psychology, psychiatry, and radiology at Columbia University in New York City.

Disclosure: Dr. Marangell is a consultant to Cyberonics, Eli Lilly, GlaxoSmithKline, Medtronics, and Pfizer; is on the speaker’s bureaus of Cyberonics, Eli Lilly, GlaxoSmithKline, and Forest; and receives research support from Bristol-Myers Squibb, Cyberonics, Eli Lilly, the National Institute of Mental Health, Neuronetics, and the Stanley Foundation. Dr. M. Martinez receives research support from Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, the National Institutes of Health, Neuronetics, and the Stanley Foundation. Dr. J.M. Martinez is a consultant to Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, and UCB Pharma; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Pfizer, and Wyeth; and receives research support from Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, the National Institutes of Health, Neuronetics, and the Stanley Foundation. Dr. George isa consultant to Argolyn, Aventis, Cephos, Cyberonics, Jazz, and Neuronetics; is on the speaker’s bureaus of Cyberonics, GlaxoSmithKline, and Parke Davis; and receives research support from Cephos, Cyberonics, DarPharma, and Medtronic. Dr. Sackeim is a consultant to, on the speaker’s bureau of, and receives research support from Cyberonics.

Please direct all correspondence to Lauren B. Marangell, MD, Mood Disorders Center, Baylor College of Medicine, 6655 Travis St, Suite 560, Houston, TX 77030; Tel: 713-798-3832; Fax: 713-798-8403; E-mail: [email protected].

Abstract

Vagus Nerve Stimulation (VNS) therapy was recently approved by the United States Food and Drug Administration as an adjunctive long-term treatment for patients with recurrent or chronic major depressive disorders who have failed at least four antidepressant medication trials. Originally introduced as an effective treatment for refractory seizures, the device was investigated as a possible treatment for affective disorders. This investigation was based on the vagus nerve’s anatomical projections in the brain; its effects on neurotransmitters, such as serotonin and norepinephrine; the use of anticonvulsants as mood stabilizers; and mood effects in some epilepsy patients who received VNS. Data indicate that long-term adjunctive VNS may improve the course of the illness for patients with major affective disorders. In general, treatment is well tolerated. The most common side effect is voice alteration and most side effects decrease or resolve with time. This article provides a clinical review of VNS therapy, including clinical trial data, side effects, and contraindications.

Introduction

Major depressive disorder (MDD) is one of the most prevalent illnesses and a leading cause of disability, affecting at least 121 million people worldwide.¹ Although an armamentarium of treatments exist, including antidepressant medications, psychotherapies, and electroconvulsive therapy (ECT), many patients with MDD continue to struggle because existing options are either not fully effective or are poorly tolerated. In July 2005, the United States Food and Drug Administration approved the use of vagus nerve stimulation (VNS) therapy as an adjunctive long-term treatment for chronic or recurrent MDD in adults experiencing a major depressive episode (MDE) who have not responded adequately to at least four trials of antidepressant therapy. The treatment is delivered by an implanted device that has been in use for adjunctive treatment of medication-resistant, partial-onset seizures in patients with epilepsy. Highlighted in this review are clinically relevant aspects of the technology, the rationale for its use in major affective disorders, clinical studies of adjunctive VNS therapy in patients with chronic or recurrent MDD to date, and recommendations for use in clinical practice, including contraindications.

The Device

VNS is administered using a pacemaker-like multiprogrammable bipolar pulse generator implanted in the left chest wall, where it delivers an electrical signal through an implanted lead that is wrapped around the left vagus nerve in the neck (Figure 1). Following the surgical implantation, the patient has two small scars, one in the upper left chest area, and one in the neck. The device itself, however, is subcutaneous and visible only upon close inspection. The implant procedure usually takes approximately 1–2 hours, and is performed under general anesthesia on an outpatient basis by a surgeon who is familiar with the anatomy of the vagus nerve and carotid sheath (eg, neurosurgeon, otolaryngologist, or vascular surgeon). The pulse generator is programmed with a telemetric wand from an external computer in an outpatient setting following surgical recovery (Figure 2). The programming is comparable to dose selection and adjustment. Adjustable parameters include pulse width, signal frequency, output current, signal-on time, and signal-off time. One example of a commonly used cycle is 30 seconds of stimulation alternated with 5 minutes without stimulation. VNS device programming can be performed through clothing while the patient is sitting in an office chair, and takes 5–10 minutes. Stimulation-related side effects are monitored in the office by observing the patient through several cycles of stimulation. Most side effects related to stimulation, further detailed below, are mild and can be minimized by adjusting the stimulation parameters while the patient is still in the office. Upon leaving the office, the device will stimulate the vagus nerve with a specified output current at the selected interval, (eg 1.0 milliAmp,) once every 5 minutes, 24 hours/day. Patients are provided with a magnet that is capable of turning the device off, if needed. The battery life ranges from 3–10 years, depending upon the parameter settings and pulse generator model.²

Rationale for Use in Psychiatry

The rationale for using VNS for the treatment of a major affective disorder was based on several observations.³ The vagus nerve sends sensory information from the head, neck, thorax and abdomen to the locus ceruleus (major source of norepinephrine in the brain), the raphe nuclei (main source of serotonin in the brain), and the nucleus tractus solitarius.^4-6 Neurochemical data indicate that VNS, like antidepressants, may increase norepinephrine⁷ and serotonin⁸ concentrations in the brain. Positron emission tomography studies during VNS in patients with epilepsy demonstrated alterations of cerebral blood flow in the rostral medulla, thalamus, hypothalamus, insula, and postcentral gyrus—areas implicated in mood regulation.⁹ Lastly, during clinical trials, investigators noted mood improvements in patients with epilepsy that appeared to be independent of the treatment’s effect on seizure frequency.^10,11

Overview of Depression Studies

The use of VNS for treatment-resistant MDD is based on an open pilot study (D01), a randomized sham-controlled acute trial (D02), and the longer-term follow-up of both of these cohorts. Both studies included outpatients with chronic or recurrent MDD (unipolar or bipolar) who were going through an MDE. Chronic MDD was defined as an MDE that was at least 2 years in duration, and recurrent MDD was defined as having at least four discrete MDEs.

Subjects had to have failed adequate trials of at least two antidepressant medications from different classes in the current episode, and at least 6 weeks of lifetime psychotherapy, to be included in the studies. In addition, subjects with bipolar disorder had to have a history of poor tolerability or non-response to lithium, or have a medical contraindication to taking lithium. Patients had to score ≥20 on the 28-item Hamilton Rating Scale for Depression (HAM-D₂₈)^12,13 and <51 on the Global Assessment of Functioning scale¹⁴ during the baseline assessment, despite current treatment. Hence, the study subjects were experiencing clinically significant symptoms and functional impairment despite standard treatments. All subjects gave written informed consent. Patients were excluded if they had a history of psychosis, cognitive disorders, substance use, unstable medical conditions, significant suicidal ideation, or a history of rapid cycling in bipolar patients. Subjects were allowed to continue existing psychotropic medications and psychotherapy as long as their medication regimen had been stable for at least 4 weeks prior to their baseline visit (ie, no new medications or dose increases were allowed, nor were new courses of psychotherapy allowed). Following the acute treatment phase, during which both medications and device parameters were kept stable, all eligible and consenting subjects entered longer-term follow-up. Medications and stimulation parameters could be adjusted during long-term follow-up, as clinically indicated. More detailed methods and study results have been published elsewhere.^15-17

In summary, the D01 study involved four study sites and 60 patients: 44 with MDD, six with bipolar I disorder, and 10 with bipolar II disorder. Subjects’ mean age was 46.8±8.7 years. In general, their current MDEs were severe (mean baseline HAM-D₂₈: 36.8±5.8) and chronic (median length: 6.8 years). Subjects had failed a mean of 4.8±2.7 antidepressant trials of adequate dose and duration in the current episode, with 26.7% failing at least seven adequate trials. Additionally, 66.7% of subjects had been treated with electroconvulsive therapy (ECT) in the past. Response rates were defined as a ≥50% reduction in the HAM-D₂₈ score, and remission was defined as a score of <10 on the HAM-D₂₈. At the end of the acute 12-week treatment phase, response and remission rates were 30.5% and 15.3%, respectively.¹⁶ After 1 year of adjunctive VNS therapy, the response rate increased from 30.5% (after acute phase treatment) to 44%, (after an additional 9 months) and was largely sustained after 2 years of active treatment.¹⁸ Of note, the remission rate also improved from 15.3%, after acute-phase treatment, to 27%, after an additional 9 months of treatment.¹⁸ However, as other antidepressant treatments were uncontrolled during that time period, changes may have been made to patients’ treatment regimens which could have accounted for or contributed to the observed benefit.

The 21-site, randomized D02 trial involved 235 patients, with 210 patients having a history of MDD and 25 patients having a history of bipolar disorder. Subjects’ mean age was 46.5±9.0 years. Their current MDEs were severe (mean baseline 24-item HAM-D [HAM-D₂₄]29.2±5.3), and had lasted an average of 4.09±4.3 years. Among the patients, 31.1% had failed two antidepressants, 25.7% had failed three, and 43.3% had failed at least four adequate antidepressant trials. Trained clinicians who were blind to treatment assignment performed outcome assessments, whileclinicians not blind to treatment assignment assessed treatment tolerability and safety, and programmed the device in a way that maintained the study blind. Outcome assessments included the HAM-D₂₄, the Inventory of Depressive Symptomatology–Self Report (IDS-SR₃₀),^19,20 the Montgomery-Asberg Depression Rating Scale (MADRS),²¹ and the Clinical Global Impression–Improvement ratings.²² At the end of the acute phase, the device was turned on for subjects in the control group who continued to meet inclusion and exclusion criteria. Therefore, subjects in both groups subsequently received active treatment, and treatment continued after the acute phase for both groups. At the end of the acute phase, there were no statistically significant differences between the D01 and the D02 group, in terms of the response rates on the primary outcome measure, HAM-D₂₄.²³

However, concordant with the results seen in the epilepsy clinical trials,²⁴ long-term follow-up of this cohort demonstrated an accrual of benefit over time. The response rate increased from 15% at acute treatment exit to 30% after 12 months of active treatment (acute treatment phase +9 months), and 33% after 24 months of treatment.²⁵ These findings were supported by data from the IDS-SR₃₀ and the MADRS. Long-term remission rates were similar, with the HRSD₂₄ showing that while only 7% of patients achieved remission upon the completion of the acute treatment phase, 17% had achieved remission after receiving 24 months of active treatment.²⁵ Seventy percent of patients who responded to the acute treatment phase were continuing to respond to treatment at 2 years, as shown by the HAM-D₂₄. Given that treatment effects were sustained for 2 years, and that response and remission rates improved over time, mood improvements are not likely due to a placebo effect, which tends to be short-lived. In addition, placebo response rates in treatment-resistant MDD are low, ranging from 0% to 10%.²⁶ Similar to the D01 study, treatment regimens in the D02 were not controlled during long-term follow-up. Changes to medications may have been made, such as the addition of a novel antidepressant or a change in psychosocial interventions, which may have affected outcome measurements.

Few data sets exist that include longitudinal data on patients with treatment-resistant affective disorders. In an effort to isolate the effects of VNS therapy on mood symptoms in the face of uncontrolled antidepressant treatment regimens, George and colleagues²⁷ compared the outcomes of patients who received treatment as usual (TAU) and VNS in the pivotal study, to subjects in another study with comparable illness characteristics, but who received only TAU. The two groups had similar demographic and clinical characteristics, including their levels of treatment resistance. Each group was followed for 1 year. In summary, remission and response rates were significantly higher for patients who were treated with VNS+TAU compared to patients who were treated with only TAU (response rates: 22% VNS+TAU and 12% TAU, P=.029; remission rates: 15% TAU+VNS and 4% TAU, P=.006), where response was defined as at least a 50% reduction in IDS-SR₃₀ scores and remission was defined as an IDS-SR₃₀ score of £14.In addition, responders to VNS+TAU had fewer dose increases or medication additions (56%) than VNS+TAU nonresponders (77%). Although this is a nonrandomized comparison, these data are consistent with a benefit of adjunctive VNS therapy for patients with treatment-resistant MDD.

Safety and Tolerability

The most common implantation-related adverse events recorded during the pivotal study included incision pain (36%), voice alteration (33%), incision site reaction (29%), device site pain (23%), device site reaction (14%), pharyngitis (13%), dysphagia (11%), and hypesthesia (11%). Most side effects resolved within 30 days.² The pulse generator and lead functioning are tested intraoperatively, and rare cases of ventricular asystole have been reported during this testing in patients with epilepsy. However, no long-term negative outcomes resulted in those cases.²⁸ The most common stimulation-related adverse events recorded during the pivotal study included voice alterations (58%), increased cough (24%), dyspnea (14%), neck pain (16%), dysphagia (13%), laryngismus (10%), and paresthesia (11%). Again, most side effects decreased over time, except for voice alterations. Stimulation-related adverse events occurring in <5% of patients included palpitations, postural hypotension, syncope, tachycardia, constipation, diarrhea, dizziness, hiccups, and rhinitis.²

Recommendations for Use

VNS therapy is indicated as adjunctive treatment for adult patients with a history of recurrent or chronic MDD who have failed at least four adequate antidepressant medication trials. Patients with treatment-resistant depression (TRD) include those with unipolar and bipolar major affective disorders. Of note, patients with rapid cycling bipolar disorder were excluded from the above studies. The effects of VNS on rapid cycling bipolar disorder are under investigation. In addition, while VNS is labeled for use in epilepsy for children ³12 years of age, its use in children and adolescents with mood disorders has not been studied.

Based on data to date, VNS therapy should be viewed as a long-term treatment, and not as an emergency intervention. Benefits from treatment with VNS appear to accrue with time. In addition, some data suggest that VNS therapy may not be as effective in patients with the most extreme treatment resistance. Specifically, a post hoc analysis of the D01 data found that subjects who had failed at least seven adequate trials of antidepressants during the current episode did not respond to VNS therapy.¹⁶ These preliminary data suggest that response might be better in patients with fewer failed treatments. As such, it is critical to provide patients and families with realistic expectations regarding the possibility of improvement, and the time frame for improvement, should it occur.

The placement of VNS therapy in the TRD algorithm has yet to be defined. There have been no trials to date that directly compare the efficacy of VNS therapy to ECT. As stated earlier, treatment with VNS is not an emergency intervention. In cases where a rapid response to treatment is necessary, physicians and their patients might consider ECT a more appropriate next step for treating TRD than VNS therapy. In addition, receiving ECT does not preclude someone from having VNS therapy in the future. Choosing between these two treatments depends upon individual circumstances and an educated discussion between each patient and his or her physician.

When deciding whether treatment with VNS is appropriate, a careful TRD evaluation is essential. Such evaluations include exclusion of underlying medical and/or substance use disorders that might be contributing to treatment resistance, as well as personality or psychosocial factors that might warrant a non-somatic intervention. Contraindications to VNS therapy include having a history of a bilateral or left cervical vagotomy and receiving diathermy.²

Conclusion

VNS therapy may act synergistically with conventional psychotropic medications to improve the long-term outcomes for patients with TRD. In general, treatment with VNS is well tolerated and there are few systemic side effects or drug interactions. However, patients and their physicians need to be aware that benefits are not immediate and, as with all treatments, not all patients respond. Further studies are needed to clarify the effects of VNS therapy on MDD and its role in treatment. PP

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