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Vagus Nerve Stimulation for Treatment-Resistant Depression

Assessment Program
Volume 20, No. 8
August 2005

Executive Summary

Depression is a serious psychiatric condition that sometimes does not respond to standard treatments such as medication and/or psychotherapy. Vagus nerve stimulation (VNS) therapy is a type of treatment administered through an implanted pulse generator and bipolar lead that has been studied in patients with treatment-resistant depression. This Assessment will review the available evidence to determine if VNS therapy is effective for treatment-resistant depression.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether vagal nerve stimulation for the indication of treatment-resistant depression meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

The NeuroCybernetic Prosthesis System (NCP®, Cyberonics, Inc.) received approval of its Premarket Application (PMA) to market from the U.S. Food and Drug Administration (FDA) on July 16, 1997, for treatment-refractory seizures. The device was approved for use in conjunction with drugs or surgery “as an adjunctive treatment of adults and adolescents over 12 years of age with medically refractory partial onset seizures.”

On July 15, 2005, the VNS Therapy System received final PMA approval by the FDA for “adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to 4 or more adequate antidepressant treatments.”

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

The available evidence is not sufficient to permit conclusions of the effect of VNS therapy on health outcomes. The available evidence consists of a case series of 60 patients receiving VNS, a short-term (i.e., 3-month) randomized, sham-controlled clinical trial of 221 patients, and an observational study comparing 205 patients on VNS therapy compared to 124 patients receiving ongoing treatment for depression. Patients who responded to sham treatment in the short-term randomized, controlled trial (approximately 10%) were excluded from the long-term observational study.

Patient selection was a concern for all studies. VNS is intended for treatment-refractory depression, but the entry criteria of failure of 2 drugs and a 6-week trial of therapy may not be a strict enough definition of treatment resistance. Treatment-refractory depression should be defined by thorough state-of-the-art psychiatric evaluation and management.

The case series data show rates of improvement, as measured by a 50% improvement in depression score of 31% at 10 weeks to greater than 40% at 1 to 2 years, but there are some losses to follow-up. Natural history, placebo effects, and patient and provider expectations make it difficult to infer efficacy from case series data.

The randomized study that compared VNS therapy to a sham control (implanted but inactivated VNS) showed a nonstatistically significant result for the principal outcome. Fifteen percent of VNS subjects responded, versus 10% of control subjects (p=0.31). There was a statistically significant result for a secondary outcome.

An observational study comparing patients participating in the randomized clinical trial and a separately recruited control group evaluated VNS therapy out to 1 year. This observational study showed a statistically significant difference in the rate of change of depression score. However, issues such as unmeasured differences between patients and nonconcurrent controls, differences in sites of care between VNS therapy patients and controls, and differences on concomitant therapy changes raise concern about this observational study. Analyses performed on subsets of patients cared for in the same sites, and censoring observations after treatment changes, generally showed diminished differences in apparent treatment effectiveness of VNS and almost no statistically significant differences. Given these concerns about the quality of the observational data, these results do not provide strong evidence for the effectiveness of VNS therapy.

Adverse effects of VNS therapy include voice alteration, headache, neck pain, and cough, which are known from prior experience with VNS therapy for seizures. Regarding specific concerns for depressed patients such as mania, hypomania, suicide, and worsening depression, there does not appear to be a greater risk of these events during VNS therapy.

3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.

The available evidence does not permit conclusions regarding the effect of VNS therapy on health outcomes or compared with alternatives.

5. The improvement must be attainable outside the investigational settings.

It has not yet been demonstrated whether VNS therapy improves health outcomes in the investigational setting. Therefore, it cannot be demonstrated whether improvement is attainable outside the investigational settings.

For the above reasons, VNS therapy for the indication of treatment-resistant depression does not meet the TEC criteria

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Vagus Nerve Stimulation for Treatment-Resistant Depression

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TEC Assessment Index

NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.

KEYWORDS: Pharmacotherapy / Therapy (category); PsychiatricDisorders (category); adjunctive; antidepressant; case series; CGI; chronic; clinical global impression; controlled; Cyberonics; D-01; D-02; D-04; depressed; depression; device; disorder; ECT; electroconvulsive; generator; Hamilton; HRSD; IDS; implant; impulse; Inventory of Depressive Symptomatology; major depression; MDD; medically refractory; mood; nerve; open label; outcome assessment; placebo; psychiatric; psychiatry; psychotherapy; pulse; RCT; recurrent; scale; sham; shock therapy; stimulate; stimulation; TRD; treatment; treatment resistant; treatment-resistant; vagal; vagus; VNS;