TEC Assessment Index
Vagus Nerve Stimulation for Treatment-Resistant Depression
Assessment Program
Volume 21, No. 7
August 2006
Executive Summary
Background
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 administered through an implanted pulse generator and bipolar lead and has been studied in patients with treatment-resistant depression. VNS was previously evaluated by the Technology Evaluation Center (TEC) for this indication in 2005 and did not meet TEC criteria. Since the last TEC Assessment, the same studies evaluated in the prior Assessment have now been published in peer-reviewed journals, and there have been some reanalyses of the same data also published.
Objective
This Assessment will review the available evidence to determine if VNS therapy is effective for treatment-resistant depression. This Assessment updates the prior TEC Assessment of VNS for the same indication.
Search Strategy
A search of the MEDLINE® database was completed for the period up through June 2006. The search strategy used the terms "depression" and "vagus [or "vagal"] nerve stimulator/stimulation" as text words or subject terms. Articles were limited to those published in the English language and enrolling human subjects. The MEDLINE® search was supplemented by an examination of article bibliographies and relevant review articles, which were searched for citations.
Selection Criteria
Articles were case series, randomized trials, or observational studies evaluating clinical outcomes of VNS therapy. In the prior TEC Assessment, results were available only from documents posted to the U.S. Food and Drug Administration (FDA) Web site. At this time, the same studies have now been published in peer-reviewed journals, almost unchanged from the FDA documents. New publications analyze the same data in various ways examining duration of benefit.
Main Results
The relevant clinical evidence evaluating VNS consists of a case series of 60 patients receiving VNS, a short-term (i.e., 3-month) randomized, sham-controlled clinical trial (RCT) of 221 patients, and an observational study comparing 205 of the RCT patients on VNS therapy to 124 patients receiving usual 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 psychiatric evaluation and comprehensive management. It has been documented that apparent treatment resistance is common due to inadequate medication or trial durations and that, for clinical trial purposes, treatment resistance should be established prospectively, not historically. Patients with clinically significant suicide risk were excluded from all VNS studies.
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) did not show a statistically significant result for the principal outcome (50% reduction in depression score or Hamilton Rating Scale for Depression) at 3 months. Fifteen percent of VNS subjects responded, versus 10% of control subjects (p=0.25). Two of 3 secondary outcome measures were also nonsignificant.
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 are insufficient to support the effectiveness of VNS therapy.
Additional reanalyses of these same data to evaluate persistence of response show that among those who achieve a response at 3 or 12 months, 60–75% of such patients are judged to remain a responder at 1 year later. In the context of relatively low overall response rates, these data do not provide evidence of efficacy.
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.
Author's Conclusions and Comments
Since the last TEC Assessment, there have been no studies reporting clinical outcomes on any new or different patients. Data from the case series and clinical trials have been reanalyzed to show what proportions of patients who respond at one time are still responders at a subsequent time point. However, this information by itself does not provide evidence of the efficacy of VNS beyond that provided by the original observational comparison of VNS versus treatment as usual.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether vagus nerve stimulation (VNS) 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) onJuly 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 clinical trials reviewed above report weak evidence that does not demonstrate efficacy.
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 its effect compared with alternative therapies.
5. The improvement must be attainable outside the investigational settings.
Whether VNS therapy for treatment-related depression improves health outcomes has not yet been determined in the investigational setting.
For the above reasons, VNS therapy for the indication of treatment-resistant depression does not meet the TEC criteria.
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;
