Vagus Nerve Stimulation Therapy Randomized to Different Amounts of Electrical Charge for Treatment-Resistant Depression: Acute and Chronic Effects

doi:10.1016/j.brs.2012.09.013

Brain Stimulation

Volume 6, Issue 4, July 2013, Pages 631-640

https://doi.org/10.1016/j.brs.2012.09.013 Get rights and content

Abstract

Background

Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD).

Objective

We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD.

Methods

In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 μs pulse width), MEDIUM (0.5–1.0 mA, 250 μs), or HIGH (1.25–1.5 mA, 250 μs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase).

Results

VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose.

Conclusions

TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.

Introduction

Depression is estimated to affect 350 million people worldwide [1]. In the United States, the lifetime prevalence of major depressive disorder (MDD) is approximately 29.9% and the 12-month prevalence is approximately 8.6% [2]. While several modalities have shown effectiveness in the treatment of a major depressive episode, a recent, large prospective trial demonstrated that 35% of patients with MDD do not respond to multiple therapeutic interventions and are considered to have treatment-resistant depression (TRD) [3].

In 2005, the United States Food and Drug Administration (FDA) approved vagus nerve stimulation therapy (VNS) as an adjunctive treatment for patients with TRD [4], [5], [6], [7], [8], [9], [10]. Despite FDA approval, some controversy remains as to the overall efficacy of VNS in TRD [11], [12], [13], [14].

VNS Therapy^® comprises an implanted electrical pulse generator with a bipolar lead and an external programming system that controls intermittent stimulation to the left cervical vagus nerve. And VNS “dosage” refers to a collection of different stimulation parameter settings, determined by a physician and conveyed via telemetry to the implanted pulse generator [15]. These parameters together determine the characteristics of electrical stimulus applied to the nerve. The parameters consist of current (milliamps, mA), pulse width (microseconds, μs), frequency (hertz, Hz), and duty cycle (amount of stimulation time “ON” [seconds] and amount of time “OFF” [minutes]). Presently, recommendations for adjusting VNS dosage in TRD patients have been based primarily on empirical observations from VNS use in medication-resistant epilepsy, and therefore, the optimum stimulation parameter settings for TRD patients are not known. The objective of this FDA-requested, post-marketing study was to compare the safety and effectiveness of VNS administered at different dosage ranges for the adjunctive treatment of TRD.

To establish a dose–response curve in TRD patients, we evaluated 3 VNS doses with variable output current and pulse width while employing the same duty cycle (30 s ON and 5 min OFF) and the same pulse frequency (20 Hz). A “low” dose was chosen to deliver active stimulation at the lowest available device settings for amplitude of output current (0.25 mA) and a narrow pulse width of 130 μs. A “high” dose (1.25–1.5 mA and a standard 250 μs pulse width) was chosen to be more consistent with the higher levels of stimulation often observed in epilepsy treatment [16], [17] and TRD trials [8]. The “medium” dose (0.5–1.0 mA, 250 μs) was chosen to track closer to the “high” dose than to the “low” dose, without overlapping the former, potentially providing a better opportunity to demonstrate efficacy versus the “low” dose.

It was hypothesized that medium-and higher-range VNS “doses”, defined by the amplitude of the output current (configured with a standard 250 μs pulse width), would be associated with superior clinical outcomes, compared with relatively “low dose” stimulation (defined by the lowest amplitude of output current and a narrower pulse width).

Section snippets

Study participants

Enrollment criteria for the study included: (1) 18 years of age or older with a diagnosis of chronic (>2 years) or recurrent (≥2 prior episodes) MDD or bipolar disorder (BP), and a current diagnosis of major depressive episode (MDE) as defined by the Diagnostic and Statistical Manual of Mental Disorders [18], and determined using the Mini-International Neuropsychiatric Interview [19]; (2) a history of failure to respond to ≥4 adequate dose/duration of antidepressant treatment trials from at

Sample characteristics

A total of 331 patients were enrolled in the study at 29 sites and implanted with the VNS system (the safety population). The first patient was enrolled on February 24, 2006 and the last patient visit was performed on February 24, 2010. Of the enrolled patients, 330 patients completed the dose titration. The 22-week acute phase was completed by 316 patients (316/331; 96%) and the 50-week long-term phase was completed by 298 patients (94% of the 316 acute phase completers) (Fig. 1).

The

General findings

This study represents the first attempt to systematically study the dose–response relationship of VNS Therapy in the treatment of TRD. In a large group of patients randomized to three different target ranges of electrical charge (LOW, MEDIUM, and HIGH groups), we did not find significant differences between the treatment groups in antidepressant efficacy during the acute phase (Weeks 8–22; primary hypothesis) or the chronic phase (Weeks 26–50). Although the effect sizes were limited,

Conclusions

Within the limits of this study design, the results demonstrated that TRD patients receiving adjunctive VNS in an open-label setting had significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year (unusual for the population being studied). The sustained improvement was in a higher proportion of TRD patients than has been seen in treatment-as-usual studies of comparable TRD populations [5]; albeit a statistically significant improvement was not

Acknowledgments

The authors wish to thank the patients who participated in the study, as well, as Amara Keerthi Jayewardene, MS (employee of Cyberonics, Inc.) for statistical analyses. Karishma L. Manzur, PhD (employee of Lenimen Consulting, Inc.) and Lorraine M. Cherry, PhD (employee of Communicate) provided medical writing assistance; both individuals were compensated by Cyberonics, Inc.

Statistical analyses were performed by Cyberonics, Inc. and reviewed by the senior author. The following principal

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Citation Excerpt :
Decreasing the output current or ON time may help with eliminating or reducing the severity of an event. A dose effect in relation to tolerability was noted in some patients at 8 to 16 weeks after implantation.28,29 Patients should be educated about potential adverse events as early as appropriate, eg, during the initial eligibility screenings.
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: Previous presentation: The findings reported in this manuscript have been reported at a symposium at Society of Biological Psychiatry on May 4, 2012.

: The study was sponsored by Cyberonics, Inc., through contracts to investigating sites.

: Conflict of interest/financial disclosure statement: We declare the following financial relationships during the past two years: Dr. Aaronson has received consulting fees from Cyberonics, Neuronetics, Eli Lilly, and Genomind, lecture fees from Neuronetics, Eli Lilly, Sunovion, and AstraZeneca, and research support from the Dalio Family Foundation. Dr. Carpenter has served as an unpaid consultant to Neuronetics, received consulting fees from Abbott, Takeda-Lundbeck, Helicon, and Johnson & Johnson. She has received research support from NIMH, Cyberonics, Medtronic, NeoSync and Neuronetics. Dr. Conway has received grant support from a K08 NIMH Mentored Clinical Scientist Award, NARSAD Young Investigator Award, and Sidney Baer Foundation, research support from Bristol-Myers Squibb, and lecture fees from Merck, Bristol-Myers Squibb, Pfizer, and Sunovion. Dr. Reimherr has received research support from Cyberonics, GSK, Otsuka, Sunovion, Pfizer, Bristol-Myers Squibb, Novartis and Eli Lilly. He owns shares in Celgene. Dr. Lisanby has received research grants from Cyberonics, Neuronetics, Brainsway, ANS/St. Jude and NeoSync, equipment support from Magstim and Magventure, and holds patents on magnetic stimulation technology (not the focus of this manuscript). Dr. Schwartz has received research funding from Cyberonics, Teva (Cephalon), and Bristol-Myers Squibb, consulting fees from PamLab, and Mylan (Dey). Dr. Moreno has received research support from Cyberonics. Dr. Dunner has received grant support from Cyberonics and Neuronetics, consulting fees from Eli Lilly, Cyberonics, Neuronetics, Cervel, Wyeth, Pfizer, and Jazz, and speaking fees from Pfizer, Wyeth, Neuronetics, AstraZeneca, and Bristol-Myers Squibb. Dr. Lesem has no disclosures to report. Dr. Thompson has received grant support from NIMH and DOD. Dr. Husain has received grant support from NIH/NIMH, NIDA, NINDS, NIA, NARSAD, Stanley Foundation, Cyberonics, Neuronetics, St. Jude Medical, MagStim (equipment only), Brainsway, and NeoSync. Dr. Vine has received consulting fees from, Eli Lilly, Forest, and Abbott. He has received honoraria from Eli Lilly, Pfizer, Forest, AstraZeneca, Wyeth, Shire, Janssen/Johnson and Johnson, GlaxoSmithKline, Somerset, Novartis and Merck. He has received grant/research support from SmithKline Beecham, Lilly Research Foundation, Organon, Janssen Research Foundation, Wyeth-Ayerst, Parke-Davis, Merck Research, and Cyberonics. Dr. Banov has received speaking fees from Eli Lilly, Pfizer, Bristol-Myers Squibb, Forest, Sunovion, and Merck. Dr. Bernstein has no disclosures to report. Dr. Lehman receives honoraria for promotional speaking from Merck, Shionogie, Purdue, Forest and Sunovion. Dr. Brannon has received research support from Sunovion, Merck, Novartis and Forest. Dr. Keepers has received research support from Cyberonics and Broaden. Dr. O'Reardon has received research support from Neosync. Dr. Rudolph was an employee (retired) and stockholder of Cyberonics. Dr. Bunker is an employee and stockholder of Cyberonics.

¹: Previously at University of Pennsylvania, Philadelphia, PA, USA.

²: Retired.

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Vagus Nerve Stimulation (VNS) and OthersOriginal ArticleVagus Nerve Stimulation Therapy Randomized to Different Amounts of Electrical Charge for Treatment-Resistant Depression: Acute and Chronic Effects

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Study participants

Sample characteristics

General findings

Conclusions

Acknowledgments

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Eur Psychiatry

J Affect Disord

Biol Psychiatry

J Affect Disord

Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States

Int J Methods Psychiatr Res

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report

Am J Psychiatry

Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes

J Clin Psychiatry

Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression

J Clin Psychiatry

Efficacy of vagus nerve stimulation in the treatment of depression

Expert Rev Neurother

Nonpharmacologic interventions for treatment-resistant depression in adults

Vagus Nerve Stimulation (VNS) and Others
Original Article
Vagus Nerve Stimulation Therapy Randomized to Different Amounts of Electrical Charge for Treatment-Resistant Depression: Acute and Chronic Effects