Vagus Nerve Stimulation for Treatment of Resistant Depression (TRD)

Dear Sir, I am in diasgreement with the NCD for VNS in refractory depression. My reasons are as follows:
(1) The focus of the review appears to be the response/remission at 12 weeks. This period is generally insufficient to obtain remission in TRD. The designers of study D02 and later the FDA realized this conceptual error. The depression treatment experts who are some of the best minds in the field supported VNS, not because many of them were part of the studies themselves but they too realized that the 12- and 24-month response/remission rates was a more suitable metric. These rates in Study D02 were between 20 & 27% for response and around 17% for remssion. For the comparison study D02 versus D04, as shown in Table 4 of the CMS review, VNS was superior to TAU on 8 of 9 measures and trended towards significance for the 9th measure.Now let us apply the above to CMS criteria for approval, namely will a treatment benefit the health of an individual. It would appear that the health of 2 or 3 out of 10 individuals with TRD would significantly benefit. The next question is the above quantum of improvement sufficient for approval. As you will quickly recognize, there is no ready answer to this latter question. I understand you have recieved more that 1000 comments from patients suffering from depression (or their care givers). Each one of them probably has a heart wrenching story of severe depression and what it has done to their life. Thus, if one is interested in approving the treatment, you would conclude imprving teh lives of 200 of these individuals is worth it. If you are not interested in approving the treatment, you will conclude 200 improved lives is not worth it.As practicing physician who sees TRD patients daily, I strongly suggest that you set the benchmark taht is set in cancer treatment, where a new treatment that will improve even 10% of lives is considered a breakthrough

(2) Now, let us apply the unique CTAF criteria to the 1- year D02 data, 1-year D02 versus D04 data and the 1-year D01 data. The CTAF criteria of equally efficacy to a standard treatment. First of all, in TRD there is no standard treatment to compare with. that is teh tragedy of this condition. We struggle everyday choosing treatments with hardly any evidence for their benefit in TRD. The best data we have is from STAR-D. At the end of one year, under the best case scenario, the 1 year sustained remission rate is around 17-18%, which is slightly lower than VNS. Thus VNS equals or beats any available treatment for TRD, with the sole exception of ECT.

(3) ECT remains atreatment for TRD. However there are many many reasons why ECT is not tolerated by many patients, is contraindictaed in some patients and refused for understandable reasons by others. In such cases VNS is avery appropriate treatment.

(4) Re: the Blu Cross tEC report, the less said the better. Whereas the CMS report pointed out the conflict of interest for the Depression experts, it did not point out the COI for Blu Cross TEC group. This group concluded at this time TRD is best assessed by state-of-the-art evaluation and management. Well D01 is a case in point. This series of cases was indeed chosen after a state-of the-art assessment fo TRD and the evidence, when the selection is careful is very much in favor of VNS. Yet, when expert clincians perform careful evaluations and treat with VNS and obtain efficacy, it is dismissed as biased or possible placebo effect. Well, you cannot have it bothways. Either the study data at 1 year (& now at 2 year) should be accepted or case series and clinican experience should be accepted. Note that the CMS review had 167 psychiatrists with experience in VNS supporting its use.

In summary, I believe the longterm efficacy of VNS has been downplayed in the CMS review and should be corrected.VNS should be covered for cases of properly established tRD and that ju

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To Whom It May Concern:

I would like to comment upon the recent ruling by CMS for non-coverage of VNS. I was somewhat concerned about the overall tone of the ruling, with respect to the implicit, sometimes explicit, biases against psychiatric research that ran through the memo. As a neuroscientist, I am well-acquainted with tearing apart data, exposing methodological flaws and highlighting uncertainty. Usually, in the case of laboratory experiments, the stakes are low, and research benefits from tough critiques and a high bar for acceptability. However, in the case of a potential medical procedure that already benefits the lives of hundreds of individuals with severe depression, and could benefit thousands more, I think that a wise individual should be able to make a complete assessment of the data, balancing clear flaws and less-than-ideal study designs with the need and importance for the treatment. But what I found in the memo was a destructive skepticism, which was not at all balanced. I do not believe that CMS carries a conscious prejudice towards psychiatric treatment, and I do not wish to besmirch the integrity of the committee that appears to be quite sincere in its belief that VNS is not an effective treatment for depression. While I am not optimistic that my comments here will change anybody's mind about VNS, I feel compelled to enter them into the record, because I am disturbed about what I see as an unconscious bias on the part of the review panel.

The proposed decision memo goes into some depth to critique the current status of assessment instruments in depression, e. g. "There is a lack of empirical evidence for endpoints in clinical studies of depression (Rush et al. 2006). Concepts ofresponse, remission, recovery, relapse, and recurrence do not have standardized, empirical definitions (Rush et al. 2006)." While I admire the scholarship of the memo, I see it being used to attack the validity of the evidence presented in favor of VNS. For sure, if we don't know how to measure depression, then how we can purport to treat it? But if the CMS really believed that we had no empirical basis for measuring depressive symptoms, then why approve any treatment for depression? If the CMS really believed that we could not measure response, what is the basis for their claim at the beginning of the memo that "There are many effective treatments for depression?" One cannot have it both ways claiming that some treatments are effective, based on the rating scales they criticize and then claim that the scales are fundamentally flawed. This is destructive skepticism, deployed to undermine legitimacy of the VNS data.

The memo goes on to dispute the idea that treatment resistance has a scientifically valid definition, e. g. " The concept of treatment resistant depression is vaguely defined, subject to varying determination, and until a scientifically valid definition exists is of little help in treatment selection for individual patients. I don't think the author of these words really thought about what they were saying, and what they implied. Yes, it is true that psychiatric disorders exist along a continuum of severity, like many chronic illnesses. Defining the borders between arbitrarily delineated concepts is a reality of psychiatric diagnosis. But disputes about where to draw the line with severity and treatment non-responsiveness do not undermine the validity of the concept.

I offer this analogy: Think of a mountain, like Mt. Rainer, that clearly rises up from other smaller peaks in the range. If you approach the mountain from miles away, walk up the foothills, above the treeline and eventually hit the summit, when do you actually walk onto the mountain? Where does Mt. Rainer begin? In fact, any declaration of where Mt. Rainer begins is arbitrary, but that hardly undermines the 'scientific validity' of the mountain. Likewise, the challenge of defining the boundaries of TRD does not mean that TRD is not a valid construct. This is not a sophisticated point to make, but to argue otherwise, as the memo does, seems a bit like sophistry. Should I tell my patients with severe, unremitting depression that their feelings have no 'scientific validity?'

We, in the field, will continue to work to find better treatments for patients who fail conventional therapy. I believe that as our understanding advances, we will find that all patients with TRD are not the same, and that we will learn how to select appropriate treatment, based on these differences. I still believe, with many others who are actually engaged in trying to help these patients, that VNS can help some of them.

Yes, the skeptic has no trouble making the point that all the data that Cyberonics has submitted may reflect noise and placebo effects. On the other hand, there may be a real signal there, a real effect that is hard to show definitively. The consequences of ignoring that signal, that potential therapeutic effect is significant.

I urge the skeptic to keep in mind one final point about VNS: VNS as a treatment for depression arose serendipitously. The neurologists who treated seizure patients had no reason to expect that depression would improve with VNS. Neurologists have plenty of experience with patients feeling better with good seizure control, but VNS was different. This is evidence, in my mind, that should go into the consideration of the data. That has been my conclusion in looking at the data. I urge you to look at all of the data from controlled studies, the history, and the even the anecdotal testimony, and reconsider your opinion.

Sincerely,

Stephan Taylor
Associate Professor of Psychiatry
University of Michigan

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I am commenting as a psychiatrist in private practice for the past 17+ years, most of that as the primary provider of ECT in a large psychiatric hospital. As a result, I have many years of experience in the management of treatment resistant depression and Bipolar Disorder. I have treated hundreds of clients who have failed many reasonable medication trials including al classes of antidepressant drugs including MAOIs, multiple mood stabilizers, atypical antipsychotics, and combinations. Some of these clients responded very well to a course of ECT but often relapsed after weeks to months. Many have been treated with continuation/maintenance ECT, sometimes for years in order to prevent frequent hospitatlization and possible suicide. They have suffered with side effects of longer term ECT including memory problems, as well as frequent trips to hospital for the procedure, repeated anesthesia, ever increasing costs, and after a time some needing increasing frequency of treatment with decreasing benefit. All this inaddition to extensive medications simultaneously. The suffering and the cost of ongoing treatment for these clients is staggering. Vagal Nerve Stimulation offers a viable option for this population. I currently have under my care 8 patients who have been implanted with the VNS, for periods varying from 1 month to over 1 year. Of those, 7 are demonstrating at least some improvement in their level of functioning and decrease in suicidal ideation and attempts. Several show a remarkable improvement in mood, affect, and level of social functioning. I have communicated with another psychiatrist in this city who has a larger cohort of implanted patients, some of whom I previously had treated with ECT, also with several robust responses and more than one complete remission. These are clients followed over many years previously, with limited improvement, frequent relapses, and aggressive medical management, psychotherapy, etc. It is my opinion that the available studies regarding VNS in this population, particularly the two-year outcome study showing response rates of 42% at two years and remission rates of 22% at two years are compelling. I believe that this represents an opportunity to reduce suffering, morbidity, mortality, and high costs of health care in a signicant number of depressed individuals. Please do not deny them this opportunity.

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As an academic psychiatrist at Creighton University School of Medicine I well know, major depression is not only the fourth most disabling condition worldwide but is also associated with increased rate of suicide and considerable economic burden. Research also shows depression is a major risk factor for myocardial infarction and stroke. Medication, psychotherapy and ECT are current options to treat depression. However, there are many patients who are resistant to treatment and do not achieve remission as well as others who experience adverse events. Vagal Nerve Stimulation for treatment resistant depression is a novel, well tolerated and valuable additional for patients. In my opinion, it is poor clinical practice and ethically dubious to withhold VNS therapy an FDA approved treatment from patients suffering chronic depression, especially those resistant to antidepressants or ECT.

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Lawrence Cohen, PharmD, BCPP, FASHP, FCCP

Please accept this letter regarding your policy related to reimbursement of VNS Therapy for Treatment-Resistant Depression (TRD). My name is Dr. Larry Cohen. I am a board certified psychiatric pharmacist with 28 years of experience working with patients with psychiatric and neurological disorders. I am currently Professor, Department of Pharmacotherapy at the Washington State University College of Pharmacy and Assistant Director for Psychopharmacology Research and Training for WIMIRT (Washington Institute for Mental Illness Research and Training). Examples of my previous positions include Director of Pharmaceutical Services for the Oklahoma Department of Mental Health and Substance Abuse Services, Director of Clinical Pharmacology Services (statewide clinical consult service for the Oklahoma Department of Human Services), and Global Director of Central Nervous System Research for Kendle International Inc., a company involved in the conduct of international clinical trials.

In a previous letter, I discussed the healthcare economics of treatment-resistant depression (TRD) and the impact that a positive coverage policy for VNS Therapy for a very specific population of these patients could have on reducing costs to the CMS system. In reviewing the proposed non-coverage policy issued by CMS, I can only conclude that the authors of the policy do not fully understand TRD and/or are not interested in providing access for these patients. In this letter I hope to further clarify the relevance of TRD to CMS, as well as discuss the benefits of access to care for both CMS and the TRD population.

What is TRD?

Comments from CMS state that the “concept of treatment-resistant depression is vaguely defined, subject to varying determination, and, until a scientifically valid definition exists, is of little help in treatment selection for individual patients”, but this description is not completely accurate.

Although it is true that there is no consistent, widely accepted definition of TRD, and no DSM-IV designation, in order to further develop “best practice” for this difficult-to-treat population, we must use the best information we have available. Investigators typically clearly describe how they define TRD along with their assumptions in their publications. In addition, the definition of treatment resistance is subject to change over time. For example, while clozapine is approved and universally reimbursed for use in Treatment-Refractory Schizophrenia, there remains debate about the threshold for treatment-refractoriness. When Kane et al published the landmark clozapine study in 1988, 2 failed treatments was thought to be adequate to describe refractoriness (Kane et al, 1988). Now, various alternative definitions have been proposed, to include failure of numerous antipsychotics of different classes, including a typical plus an atypical. Nonetheless, there remains a substantial population of patients with treatment-refractory schizophrenia by any definition, and clozapine continues to be prescribed and routinely reimbursed. My point is that the definition of treatment resistance may change with time, as fewer treatments are developed, but the population will still exist. The same should hold true for Treatment-Resistant Depression and VNS Therapy. The concept of TRD has become better defined recently through STAR*D, an NIH project designed to evaluate step-wise treatment of depression. Through numerous publications over the last 2 years, we have learned that after 2 failed treatments, the chance of success with a 3rd or 4th antidepressant is negligible. (Rush AJ et al. 2006a) Thus, the definition of TRD would logically be the failure of 2 antidepressant treatments, based on findings from STAR*D. Other definitions have certainly been proposed, such as the multi-stage definition developed by Thase and Rush (Thase and Rush, 1995), however, the data from STAR*D as described above provide, for the first time, an empirical basis for the designation of treatment-resistant depression. It has been my impression that the requestor has taken a very conservative approach in identifying the most difficult, severely impaired patients for their studies, who would meet any reasonable definition of Treatment-Resistant Depression. FDA labeling is consistent with this approach, and the VNS indication for TRD requires a minimum of 4 failed treatments, making this a subset of the TRD population.

CMS also remarks that the “methods used to measure treatment progress lack standardization, and are inadequate to reflect the complexity of the disorder.”

The scales most often used in depression trials are the HAM-D, MADRS and IDS; all have been validated and although they may not be ideal, as pointed out by the ACNP Task Force on Response and Remission (Rush J et al, 2006b), are the best we have and are widely used in clinical trials and routinely in some academic centers in order to develop a clearer understanding of disorders such as TRD. In fact, regulatory agencies such as the FDA require that validated scales such as the HAM-D (also referred to as the HRSD) be included in a submission. Support for development of new validated sensitive instruments could in fact be an area worthy of investment by the NIH, as improvement in the management of depression has impact on overall health. For example, we know that untreated depression may worsen outcomes associated with a variety of chronic conditions, diabetes (Erin I et al 2007), cardiovascular disease (Frauere-Smith and Lesperance 2006), and stroke (Salaycik et al, 2007) although these medical comorbidities and considerations are rarely included in economic studies of the impact of behavioral disorders such as depression. In fact, exclusion criteria frequently eliminate patients with medical comorbidities from clinical trials.

Further, CMS stated, “It was approved by the FDA for patients who had failed four antidepressant treatments. Additional requirements have been suggested, by the requestor, for coverage in those previously treated with or refused treatment with ECT or who have been previously hospitalized for depression. These various indications without scientific basis illustrate that the term treatment resistant depression lacks a standard definition that has been scientifically validated, and appears to be subject to arbitrary interpretation.”

Although there is no uniformly accepted definition of TRD, typically in clinical trials the definition and assumptions are clearly described. Definitions have been as lenient as one failure of an SSRI to four antidepressant treatment failures at an adequate dose and duration (with antidepressants from at least two classes) AND previous treatment with ECT and/or hospitalization. The FDA approval for use after 4 failed antidepressant treatments coupled with the requestors additional conditions of hospitalization or failure or refusal of ECT ensures that VNS will be used in only the most clearly resistant population.

In an analysis of a claims database from a large national employer, Greenberg et al found that patients with TRD incurred greater than twice the costs of patients with non-resistant depression, and greater than 3 times the cost of the general population (Greenberg et al 2004). Identical findings were described earlier by Corey-Lisle in a separate database(Corey-Lisle et al 2002). In another analysis of the economic impact of TRD, Russell et al described increasing health care costs as the number of antidepressant switches (assumed to be failures) increases. (Russell et al 2004) The bulk of these increased costs were due primarily to hospitalizations and increased direct mental health costs. Patients previously hospitalized or who have received ECT are among the most costly and treatment resistant of all patients receiving services whether by private insurance or through government-funded programs. Crown et al, using a MEDSTAT database found that TRD patients with a history of hospitalization incurred over 6 times the cost of non-TRD patients and 4 times the cost of outpatient TRD patients annually. (Crown et al 2002). The fact is, as these previously employable productive citizens become more severely ill, they are at work less frequently and when they are, they have significant reductions in their productivity, hence presenteeism becomes a larger concern of employers. In the long run, they may become less likely to remain employed and ultimately become the responsibility of CMS through disability and other channels.

Access – “Is the evidence sufficient to conclude that, in the Medicare population, vagus nerve stimulation will improve health benefits for individuals with treatment resistant depression?” Based on the data submitted from the pilot and pivotal studies in the long term, VNS should result in lower overall lower health costs. This is described in detail in my previously submitted comment. In addition, availability of VNS for non-Medicare insured may delay TRD patients from becoming Medicare recipients by improvement in absenteeism and presenteeism; however, further research is needed. In closing, it is my opinion that policies opposing universal access to VNS Therapy for clearly defined TRD patients in need of treatment appropriately prescribed by well-informed providers may in the long run be costly. One group of patients whose treatment with VNS would potentially result in significant cost savings would be patients with TRD who have failed 4 antidepressant treatments and who have been previously hospitalized for depression or treated with or refused ECT. Currently, patients with chronic and recurrent treatment-resistant depression must pursue an arduous path of appeals that may or may not be successful, whereas patients with medically refractory epilepsy benefit from near universal access to VNS Therapy.

Thank you for considering my comments.

Lawrence J Cohen, PharmD, BCPP, FASHP, FCCP
Professor,
Department of Pharmacotherapy
Washington State University College of Pharmacy
Assistant Director for Psychopharmacology
Research and Training
Washington Institute for Mental Illness Research and Training

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Response to the CMS Proposed Decision Memo for VNS

I am writing regarding the recent proposed decision for VNS because I was cited in the section on rating change in depression and because I participated in the CTAF hearing as an invited expert.

I do not dispute the principal finding that the sham controlled study of VNS failed to show superiority over placebo on the primary outcome measure. The low rates of response in this study are not altogether surprising given the subsequent findings of the STAR*D trial namely that response rates progressively decline with each treatment. After four previous trials low response and remission rates would be expected and the VNS study was underpowered.

What was surprising in this report was the gratuitous and apparently self-serving criticism of the diagnosis of depression and the methods used to evaluate treatments for this disorder.

March 7, 2007

Centers for Medicare and Medicaid Service
Att: Beverly A. Lfton, MHA
7500 Security Boulevard
Baltimore, MD 21244

Dear Ms. Lofton:

Ref: NCA for Vagus Nerve Stimulation for Treatment of Resistant Depression (TRD) (CAG-0313R) C1-09-06.

On behalf of the Mental Health Association of Tarrant County, Texas, I am writing this letter to support making the option of the Vagus Nerve Stimulation available to the individuals who need such and for whom all other treatment for depression has failed.

As a community-based agency that provides information, referrals, system navigation, supported employment, individual advocacy and consumer support to persons with all kinds of mental illness, we have certainly encountered a number of individuals dealing with what appears to be treatment resistant depression or TRD. Fortunately this seems to be a small percentage of folks, but it is clearly a real phenomenon for a desperate few. In the course and scope of our services, we work to not only help individuals in need find good appropriate services in this community, but also strive to give our callers and consumers hope and encouragement that there is something that will help them and their future to be better. Unfortunately, for those who have already tried numerous anti-depressant drugs and/or psychotherapy of various kinds, this hope is elusive and almost non-existent. In fact, we have a colleague and former employee of this organization who deals with TRD, and as a result of this disabling condition, she left our agency, and went on disability. We understand she is waiting—and hoping for Medicare to approve the VNS procedure for her.

We are well aware that VNS is an expensive treatment modality, and understand of course, that would be a factor in Medicare and Medicaid’s approval of such. However, there is almost always an increased cost related to other medical care when depression is not / cannot be adequately treated and reduced. The National Institute of Mental Health (NIMH) has determined that depression is as important a risk factor for heart disease as is high blood cholesterol and high blood pressure. And then there is the enormous cost to families, employers, communities and our society when an individual is unproductive, unable to work and handle responsibilities because of untreated depression. This takes a toll in community dollars, over-utilization of public services, lost lives and families. According to the National Committee for Quality Assurance, American employees use over 8 million sick days a year due to untreated or mistreated depression. Additional research by NIMH determined that employee absenteeism due to depression cost U.S. business billions of dollars every year.

In our efforts to promote and enhance mental health of this community and beyond, we think depression can and should be treated whenever and however it can be. Therefore, we would urge the Centers for Medicare and Medicaid Services to allow and cover the use of VNS as a therapeutic modality for that small group of individuals who critically need such.

Thank you for the opportunity to offer these comments at this time.

Sincerely,
Linda L. Ragsdale, LMSW
Executive Director

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March 7, 2007

Dear Dr. Phurrough,

We are board-certified psychiatrists at Wake Forest University Health Sciences, a participating provider with Medicare/Medicaid. We write this letter regarding CMS’ recent policy decision governing approval of Vagus Nerve Stimulation Therapy for patients with treatment-resistant depression (TRD). Quite frankly, we are dismayed that the individuals most severely affected by major depression are being denied access to a potentially life saving procedure. We have reviewed the non-coverage documentation and it is in a word, shameful. Shamefully short-sighted, unscientific and discriminatory toward those with a mental illness. To find that CMS has chosen to include in the analysis anonymous internal reviews from private, for-profit health insurance carriers shows clearly the bias against this treatment is based principally on the expected economic impact. To find CMS actually questioning the concept of treatment resistance and time honored rating scales in the evaluation of depressed patients is astounding. To give these arguments credence is to question the value of other established antidepressant treatments, for which coverage is already provided based upon these same outcome measures.

In our tertiary care clinic, we treat patients with significant TRD and have referred four patients who have received the implant but for whom reimbursement was denied. Three additionally have been denied access to this treatment by Medicare. All of these patients have had little or no response to numerous antidepressant medications and five have had multiple courses of treatment in Electroconvulsive Therapy, with partial response that was temporary, or no response at all.

Our experience with those receiving the implant is in keeping with the data submitted and approved by the FDA but rejected by CMS. We have been scrupulous in selecting only those who are clearly treatment resistant via ATHF treatment adequacy criteria. Five out of 10 have shown some clinical response and for two persons have achieved a remarkable remission. One patient denied access to an implant committed suicide. Hopelessness is real and as it turns out, quite measurable.

We are not sure the value of writing this comment at this time except to vent frustration because we have no confidence that the CMS process in reaching the NCD was at all deliberative nor responsive to the opinions of those of us who work with this patient population. Earlier comments made by experienced psychiatrists in our department and others around the country, including the American Psychiatric Association were never seriously considered. We are writing today just to go on record. The effect sizes seen with VNS are consistent with expensive and invasive treatments for metastatic cancer for which Medicare provides coverage. We can only conclude that this non-coverage decision is evidence that CMS does not value depressive disorders on a par with other chronic illnesses.

It is unlikely that our words will affect how individuals responsible for this ill-advised decision to stifle innovation in the treatment of major depression view their actions today. It is human nature to hide one’s true motivation behind a cloak of carefully worded justfications. Sadly, we can see through this thin veil to reveal the intent to save a little money at the expense of America’s seriously mentally ill—there is plenty of room on that bandwagon to be sure. Rest assured, we perceive these motivations quite clearly.

Our U.S. representatives charged with Medicare oversight on the Senate Finance Committee and the Congressional Ways and Means Committee, membership are copied on this letter and the chances are quite good and statistically robust that a number have family or friends or that they have themselves been affected by a mood disorder. That there are many constituents harmed by this decision is an absolute certainty. We can only hope that they bring their influence to bear in reversing the bias that mental illness is not real illness, born of ignorance and perpetuated by smug certitude or vain hope that it can’t happen to me.

Stephen I. Kramer, MD
Associate Professor

W. Vaughn McCall, MD, MPH
Professor

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I have now personally treated a number of patients with VNS.

A significant number have made very significant improvement. This change has been slow inoccurring , but some it has been a life altering event.

I continue to be concerned about treatment resistance is defined, but a definition that provides this as an option fora limited number of patients is very important.

Conversely, the ositive results that I have seen are much clearer in patients who are reasonable and limited sets of medications.

In these patients VNS, has had a relatively high success rate.

Such a treatment approach would also be cost effective in the long run considering costs of ongoing medical care.

Fred Reimherr, MD
University of Utah

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On behalf of NAMI-DE Board members and our general membership, I want thank you for the opportunity to submit a public comment in support of the Vagus Nerve Stimulation (VNS) for Treatment of Risistant Depression (TRD).

Our grassroots organization was distressed that CMS made a determination that VNS would not be available to individuals suffering from treatment resistant depression (TRD). Mental illness is a neurological brain disease just as is seizure disorders and deserves the same unrestricted access to treatments as any other brain disorder.

NAMI-DE supports open access to all FDA approved medications and treatments for mental illness. We believe that it is the responsibility of the individual psychiatrists to recommend or prescribe to their patients that they feel will most benefit the individual patient. We also believe that psychiatrists should have unfettered access to all FDA approved treatments.

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I am writing to express continued support of coverage by CMS of Vagal Nerve Stimulation (VNS)for patients with treatment-resistant depressive disorders severe enough to require ECT, become lifethreatening through suicidal plans or inability to self-care, and thus require hospitalization. I am speaking from my perspective as the Director of the Affective Disorders Program at Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, and as President of the NH branch of the American Psychiatric Association. I have reviewed your proposed decision carefully. I applaud your decision to consider coverage with evidence development. However this will cover only those few Medicare recipients lucky enough to receive care near a participating academic center. We know from the well-conducted and analyzed STAR*D trial that depression severity scores correlate with socioeconomic status and likelihood of receiving Medicare or Medicaid benefits, which makes perfect sense. Severe depression is a debilitating life threatening disease with severe morbidity and mortality not only for the patient but for the families involved. The economic loss associated with severe depressive disorders is astounding.

I believe, based on the existing data, that until there is a substantial post-approval data base that demonstrates effectiveness profiles for VNS response, VNS should be reserved for those with severe depression as noted above. I believe that there should be a recommended assessment protocol for all patients receiving implantations at this stage of knowledge, so that we can gather quickly and efficiently the data needed. I believe that when other treatment options with proven efficacy exist for a patient these should be tried prior to VNS. CMS states "CMS is proposing that there is sufficient evidence to conclude that vagus nerve stimulation is not reasonable and necessary for treatment of resistant depression." For many patients who have not responded to other available treatments it is the only treatment for their treatment-resistant depression.

In closing, I would like to share a clinical encounter with a cancer patient suffering from melanoma with multiple sites of metastasis. As he fights for his life, he described his most recent chemotherapy protocol. The chance of remission, he said was 5%, the chance of response was 30%. He said each dose cost over $20,000. He said he was grateful to the field of medicine and to his insurance company for giving him every chance to live. Do patients with severe treatment resistant depression deserve less?

Sincerely,
Sally Ricketts M.D.
Director, Affective Disorders Program
Department of Psychiatry
Dartmouth-Hitchcock Medical Center
Lebanon, NH

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I have one patient with a VNS implant as he is the only patient I have been able to get approved by third party payors. He is significantly improved after failing several classes of antidepressants, psychotherapy and electroconvulsive treatments. His response to VNS therapy has been sufficient to the point we have been able to reduce the number of medications we were attempting to use to stabilize him. His number of days off work have decreased, as has the number of occupational accidents he was having. The cost savings in elimiating other less effective treatments will result is an overall savings n direct costs, and his increased productivity and fewer accidents will decrease the indirect costs of his depression. Further costs savings with effective treatments for refractory depression, including VNS, are realized in the reduction of the impact depression has on co-morbid illnesses. If depression is not effectively treated, there is increased costs in treatments for other illnesses such as diabetes, heart disease, lung disease, cancers, and almost all other illnesses.

The denial of VNS, an approved FDA treatment for refractory depression, serves to increase, not decrease, the cost of health care. I sincerely hope you will take a closer look at this cost effective treatment for its overall savings to health care in the long run, rather that the immediate savings of arbitrarily denying it to avoid an immediate specific expenditure.

Respectfully submitted,

Wesley D. Richardson, D.O., F.A.C.N.
Board Certified Psychiatrist

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For nearly 100 years, Mental Health America (formerly the National Mental Health Association) has been the nation’s leading organization working to focus attention on the mental health needs of all Americans. Our mission is to improve the mental health of millions of people though advocacy, education, research and practice. Our programs reach out to people of all ages and address all aspects of mental health, including wellness, prevention, treatment and recovery. We are especially concerned with promoting access to effective and appropriate treatments for persons with mental illnesses such as depression, bipolar disorder and for those at risk of suicide.

We work to remove barriers to treatment for adults and children with mental and substance abuse problems. To that end, we are committed to drive legislation, policy and practice to assure that people with mental illnesses achieve parity in access through our healthcare system. Our mission demands that we advocate for equal access to any and all FDA-approved treatments.

The purpose of this letter is to make clear our position regarding treatments for depression and more specifically, the 20% of persons whose depression has not responded to multiple interventions. In reviewing the FDA’s Decision Summary of February 2007 we were particularly concerned with your discussion of the definitional issues with TRD:

“Depression is a disorder whose etiology is not completely understood. Comorbidities are common with this disorder and can complicate treatment. Treatments of proven effectiveness do exist, though there is little information to guide clinicians in medication selection depending on individual patient characteristics, and what to do if initial treatment fails…” “…The concept of treatment resistant depression is vaguely defined, subject to varying determination, and until a scientifically valid definition exists is of little help in treatment selection for individual patients….”

The FDA’s position seems to be that TRD must be more scientifically defined than depression is at present. This constitutes a potential double standard for persons whose depression does not respond to standard treatments. Persons suffering from TRD face a life ruining and often life threatening condition. All too often people with TRD are unable to work, utilize vast healthcare resources, and have a high mortality rate: 15% end their suffering through suicide. In arriving at a conclusion that a person has TRD, it is clear that other treatments will have been tried. This will always be an inexact process of trial and error, and a clinical judgment between patient and physician, no matter how “scientific” the definition of TRD. We strongly encourage Medicare to help eliminate limit mental health disparities by ensuring that all persons with mental illness, including TRD have access to the full range of FDA-approved treatments for their illness.

Sincerely,

Raymond L. Crowel, Psy.D.Vice President, Research and Practice

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I am writing on behalf of the Association for Behavioral Health and Wellness (formerly the American Managed Behavioral Healthcare Association). ABHW is an association of the nation’s leading behavioral health and wellness companies. These companies provide an array of services related to mental health, substance use, employee assistance, disease management, and other health and wellness programs to over 110 million people in both the public and private sectors.

In September we wrote that we did not believe the data established the effectiveness of vagus nerve stimulation for treatment resistant depression. To our knowledge there has been no new evidence to support its efficacy. As a result, we support CMS's conclusion that there is insufficient evidence to conclude that vagus nerve stimulation is reasonable and necessary for treatment of resistant depression and at this time we also support their decision to issue a national noncoverage determination for this indication.

Thank you for your consideration and the opportunity to comment.

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March 7, 2007.

Re: VNS therapy access.

To whom it may concern:

I am greatly concerned over the non-coverage draft decision issued on February 5, 2007 denying coverage of Vagal Nerve Stimulator therapy for patients with treatment refractory depression. I am acutely aware of the percentage of patients who do not have an adequate response to traditional treatments for chronic severe depression and currently have five patients whom have benefited from VNS implantation for treatment refractory depression.

While I am aware of the cost of this treatment and certainly would agree that one of the responsibilities of a physician is to be a good steward of the nation's health care dollars, it is unethical to deny the limited number of patients appropriate VNS therapy access to this treatment option based on costs. After all we do not do this when it comes two surgical procedures cantor treatments or for her use of vagal nerve stimulator therapy for treatment resistant epilepsy.

I am asking that you give careful consideration to reversing decision to deny coverage for this form of treatment as it represents an important clinical tool in effectively treating individuals with treatment resistant depression.

Respectfully submitted,

Charles Shelton D. O.

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I hope we can agree that major depression is the most painful of human experiences. Think of it – this is the one medical condition which robs an individual from the natural “survival instinct” leading to extinction by suicide. In these instances, essentially, depression is a terminal illness with the exception that death is not by natural causes.

I write to you out of concern about the current CMS Medicare decision regarding treatment with Vagus Nerve Stimulation (VNS) and what will happen to existing VNS implanted patients as they will need intermittent monitoring and dosing post your adverse decision. The Food and Drug Administration (FDA) originally approved VNS Therapy in 1997 for the treatment of medically refractory epilepsy (MRE). On July 15th, 2005, FDA expanded the labeling of VNS Therapy to read: “for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.” Regrettably, the CMS non-coverage determination for VNS in depression effective leaves all patients with treatment resistant depression (TRD) and currently implanted patients in serious jeopardy.

What we know about depression is that 70-80% of patients with depression are able to receive successful treatments for their mood disorder efficiently and effectively with full recovery and limited impact on their quality of life and work productivity. However, there is still 20-30% of affected individuals for whom it is a chronic and disabling state. In this group, there are multiple failed trials of medications and psychotherapy over prolonged periods of time. Some estimate this group to account for almost 50% of the treatment resources for depression which is typically due to high medication costs. This can be attributed to treatments consisting of multiple medications and multiple psychiatric admissions. A subgroup of these patients with treatment resistant depression cost their employers about $15,000/year with added costs incurred due to work loss. The costs are even higher in patients who have required hospitalizations with figures cited as high as $43,000. When all the medical, absences, short-term disability, and presenteeism costs are added together for chronic medical conditions, depression ranks highest second only to heart disease and hypertension.

Recent advances in the neurobiology and treatment of depression provide hope for such patients. In July 2005, the FDA approved the Vagal Nerve Stimulation Therapy system from Cyberonics, specifically for treatment resistant depression. This treatment has been available for medically refractory epilepsy for years and it has now been made available as adjunctive therapy for their equivalent cohorts in psychiatry with depression. While it is clear that no single treatment fits all, VNS is an important tool in this difficult to treat group that has end stage depression. In other words, this is no different than dialysis in ESRD, or ventricular assist devices in end-stage cardiac failure. It is to be used in conjunction with psychotherapy, psychosocial rehabilitation, and medication treatments.

Given the lack of effective treatment alternatives in Treatment Resistant Depression, the cost-effectiveness of VNS Therapy in TRD is even greater. One such study (VNS/epilepsy) conducted by the Kaiser Permanente in California examined utilization, direct and indirect costs before and the year after VNS Therapy. Study results showed significant reduction in the following areas when comparing one year utilization pre-VNS Therapy implantation through four years post-implant:

Please consider keeping VNS as a valid, FDA approved treatment for people with treatment resistant chronic/clinical depression. Useless suicides occur from untreated/poorly treated severe depression.

Please save lives and make the lives of those living with chronic depression who need/respond/or choose this VNS treatment available to them and their doctors.

Anyone who has ever been in a suicidal, severe depression knows the pain that one endures during these cycles of time, lost to depression and symptoms that can be helped or even eradicated in some instances with proper treatment.

I think VNS is a valid treatment that should remain an option to the patient and his/her doctor.

Sincerely,
Karen Brown

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VNS provides hope for people fighting debilitating depression. These are people who have lost their quality of life, fighting suicidal urges often on a daily basis. For TRD candidates, other forms of treatment have not been successful. They are on a journey to find a treatment that will restore their lives. According to research, VNS has been successful. While the degree of success is still being determined, those that have benefitted are living happier, more productive lives. Eliminating coverage of VNS will close a door for those people it would help in the future. Hope is the one thing they have with which to fight depression. To diminish that hope is an injustice to TRD patients, and for the rest of us who, by luck or by grace, are not afflicted with debilitating depression. Thank you.

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I am a Psychiatrist in Springfield, MO. My practice has several patients with severe depression who have either not responded or responded very minimally to medications and even ECT. Many of these patients have unremitting unipolar and bipolar depression.

I have been using VNS for depression over the last year and the results I have observed have been truly phenomenal. Every patient with the implant has improved dramatically, with significant reductions in MADRS scores and complete resolutions of suicidal ideation. My patients have also reported better memory, focus and renewed interests in things that they had ceased to care about for several decades. One patient, who had repeated hospitalizations almost every month has been stable as an outpatient for more than six months since she has had the implant. This alone has already paid for any cost incurred with the VNS device.

I believe it would be short-sighted to deny coverage for VNS. It is destined to be the most revolutionary treatment for treatment-resistant depression since ECT and may even exceed ECT in its eventual efficacy. Enormous cost in the form of the burden of repeated hospitalizations, life-long medications and loss of valuable work-hours with draining disability payments would be avoided.

Patients with this disabling illness desperately need any hope they can get. VNS provides this hope and the promise of a better, more fruitful life.

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March 7, 2007

Dear Sir/Madam,

RE: Vagus Nerve Stimulation for Treatment Resistant Depression

I am extremely disappointed as both a physician and researcher in the CMS comments regarding proposed non-coverage for Vagus Nerve Stimulation for Treatment Resistant Depression (CAG-00313R). Moreover, it is unacceptable that the report has misinterpreted and referenced my work to support conclusions that are incorrect. Such references disregard 50 years of psychiatric research and show a lack of understanding by the reviewers about Major Depression and Treatment Resistant Depression, in particular. Allow me to highlight a few such instances from the CMS draft:

The report states “The definitions of treatment resistance, treatment response, and remission are variable. Rush (2003) proposed that, “Difficult to treat depression includes depression that inherently does not respond satisfactorily to one or more treatments that are optimally delivered (treatment-resistant depression) and also depression treated under circumstances precluding the optimal delivery of potentially effective treatments. Such circumstances include the use of subtherapeutic doses; nonadherence; intolerable side effects that prevent an adequate dose or duration of treatment; and concurrent Axis I, II, or III conditions that reduce the likelihood of remission for adherence, pharmacokinetic, or pharmacodynamic reasons.” Note that the above refers to difficult to treat depression in which includes but is broader than treatment resistant depression (TRD). TRD refers to patients who are properly diagnosed, given appropriate medication doses for adequate time periods. These are the patients who entered the VNS trials.

The recent multi-site NIMH STAR*D trial clearly reveals that TRD is an important and clinically definable entity (Rush AJ et al. Am J Psychiatry. 2006;163:1905-1917). Remission rates after steps 1 and 2 are 36.8% and 30.6% respectively, but fall steeply to 13.7% at Step 3 and 13.0% at Step 4. These data makes the case that a "scientifically valid definition" of TRD would be failure of 2 or more antidepressants. Definitions of treatment response and remission are largely not variable in depression research, which I will address below.

It is true that there can be many root causes for “difficult to treat depression”, as distinct from TRD, which may include underdosing, intolerable side effects and concurrent conditions. The inclusion/exclusion criteria for the D-02 trial were thoughtfully designed to eliminate inadequately treated patients from enrollment. The Antidepressant Treatment History Form was used in determining whether a patient was treatment resistant. This measure incorporates the length of treatment and the dosage defining treatment resistance. As an example, for someone to be considered resistant to fluoxetine, a patient would need to have been treated with a dose of at least 20 mg for a minimum of 4 weeks. In addition to failing 2 antidepressants from 2 different classes by ATHF criteria, the VNS patients were required to have failed a minimum of 6 weeks of psychotherapy (Rush et al, 2005a). For a trial to be considered adequate, per ATHF criteria, a patient must have been adherent to therapy. Any evidence of noncompliance or discontinuation due to adverse effects in the context of significant clinical improvement diminishes the rating of trial strength. Concurrent Axis I, II or III conditions that may reduce the likelihood of remission were addressed in D-02 by specific exclusion criteria, designed to eliminate these patients.

The CMS report misrepresents my recent article (Rush, et al, 2006). This article, written years after the VNS trials were begun, was aimed at urging the field to improve upon the longstanding and widely accepted definition of response and remission. Response defined by a > 50% reduction in baseline symptoms has been used as an outcome in many FDA and NIH trials. It is associated with substantial functional improvement (Miller, et al., 1999). Remission too has been defined and accepted for some time as a valid endpoint (Miller, et al, 1999; Rush, et al, ACNP Task Force Report, 2006). The ACNP Task Force Report on Response and Remission in Major Depressive Disorder simply aimed to focus the field on trying to improve upon these longstanding, well accepted endpoints. Until better definitions of response are developed and empirically studied, it is appropriate to continue to refer to a > 50% reduction as a response. Definitions of remission involve cutoffs on validated rating scales to establish the lack or absence of depressive symptoms. For example, remission has commonly been described as a HRS-D17 less than 7, HRS-D24 less than 9, or an IDS-SR30 less than 14. The field has adhered to these above cutoffs, as was done in the D-02 and D-04 studies. The Task Force has recommended using scales that identify all nine DSM-IV criterion domains for depression to operationalize remission. D-02 did this by including the IDS-SR30 among it’s outcome measures.

As noted in the CMS report, the Task Force did, indeed, recommend that 12-20 week trials be used to evaluate remission. Although the ACNP report mentions that longer trials may have an increased risk of spontaneous remission, the likelihood of this is low in a chronically ill treatment-resistant group, such as was studied in D-02. The Task Force recommended that both response and remission criteria be met for 3 consecutive weeks, however, it was also noted that, in practice, this may be impractical (Rush et al, 2006). In a long-term study such as D-02, this would require weekly visit for 52 weeks and would place an undue burden on subjects and clinicians, ultimately affecting the ability to recruit and retain subjects. Still, in the spirit of this recommendation, D-02 results were reported for “sustained response”, using HRS-D24 data for months 9, 10, 11, and 12. At least one of these visits had to show a 50% or greater improvement in score, and 2 others had to show a 40% or greater improvement in score. By this definition, 26.6% of the completer sample showed “sustained response”, nearly as many as were defined as responders (29.4%) (Rush AJ et al, 2005b). To put this another way, of 52 total responders, 47 were sustained responders. This gives reasonable assurance that these patients were truly in response, and not merely exhibiting transient improvement in symptoms.

Contrary to statements in the CMS proposal, the association of symptom reduction with improvements in functional outcome has indeed been shown in numerous studies, as reported by the Task Force (Rush et al, 2006). Despite this finding, it is not appropriate to tie functional improvement to outcome, as other concurrent conditions (Axis I, II and III) after functional outcome as well. In addition, it has been reported that there may be a significant time lag between symptom response and functional improvement, making it difficult to evaluate in a research setting (Rush et al, 2006).

By reporting results using a variety of rating scales along with standard definitions of response and remission, D-02 results are more easily put into context with other depression trials. While the ACNP Task Force provided useful suggestions for improving upon the way we now define response and remission, ideas were put forth as proposals for improving upon what we already know. As noted in the ACNP Report, the recommendations put forth by this panel, while guided by reason, clinical experience and logic, are not evidence-based. Rather, they are put forth as recommendations that should be viewed largely as hypotheses in need of empirical study (Rush et al, 2006). Until such studies are designed and analyzed, it is appropriate to continue using the established definitions currently adhered to in depression research.

The CMS report states “The authors defined a group called the observed sample, where only participants with data available for each measurement at each time point were included, which is the reason they give as to why the number of people evaluated for different outcomes vary.” The observed sample was created to better describe data that existed at each time point, as some patients had missing measures and some had dropped out. Since it appears that the benefits of VNS Therapy increase over time, it is important for the data to represent the true sample at the later time points in the study. However, looking at the Observed Sample and LOCF data side by side, there were very few differences between these samples. In fact, the total HAM-D, MADRS and IDS-SR scores at 12 months were all significant (p<0.001) when compared to baseline in both the Observed and LOCF samples. The percentage of responders and remitters, as measured by the HAM-D, MADRS and IDS-SR, for the Observed Sample and LOCF groups were also similar at 12 months (Rush AJ et al, 2005b). In summary, the a priori defined Observed Sample provided insight into the effects of VNS Therapy over time. Most importantly, this data tracked very closely with corresponding data from the LOCF sample at 12 months.

The report also states that “other issues add to the difficulties with interpreting the D02 studies: inconsistent reporting of data between publications and FDA public documents; lack of rigor in patient selection; measures and endpoints that are clinically ambiguous; and concomitant adjustment of other treatments (D02 long-term study). Detailed inclusion/exclusion criteria were listed only in the FDA Clinical Memorandum. It is unclear why certain criteria were chosen, and some criteria appeared subject to broad interpretation. Inclusion criteria included: “…must have had an unsatisfactory response to at least two adequate trials of different classes of antidepressant medication, but not more than six, regardless of antidepressant category based on participant/family interviews, medical records, and, when available, pharmacy records” (Rush et al. 2005a). The attainment of Antidepressant Therapy History is questioned: in a recent study, the accuracy of patients recalling prior treatment with antidepressants revealed that about 80% remembered monotherapy correctly, while only 25% recalled augmentation therapy correctly (Posternak et al. 2003); a medical record review of Medicare patients receiving mental health services revealed many medical records were found to lack adequate documentation, with no documentation for billed visits in some cases (Office of Inspector General 2001). “

The 1st sentence makes a number of claims which upon further scrutiny, apparently have no merit. Incredibly, my quote actually counters the claim that patient selection lacked rigor. It is true that patient recollection may not be 100% accurate in describing past antidepressant treatment, particularly in the case of patients with TRD who may exhibit cognitive deficits and have had numerous past treatments. It is for this reason that family interviews were conducted, medical records were obtained and pharmacy records were pursued (which was helpful in establishing compliance via refill history). There are very few depression studies ever conducted that have comparable rigor with regard to patient selection. As already previously indicated in my answers, the statement that measures and endpoints are clinically ambiguous is simply false and inconsistent with the past 50 years of psychiatric research. The supposed inconsistencies between our papers and the quoted FDA documents likely have to do with different time frames (and perhaps definitions) being used. In our papers, we would routinely report safety events only through the duration of the trial being discussed (e.g. for 3 months for the acute trial paper and 12 months for the long-term paper); whereas, the FDA (for very good reasons) might choose to look at safety data beyond such arbitrary time frames. For that matter, detailed inclusion/exclusion criteria are not available only from FDA memos, but can be obtained from a number of sources. The long-term adjustment of concomitant treatments is a valid concern and one which was looked at extensively (and discussed extensively with the FDA prior to their ultimate approval of VNS); though the complete data regarding this point is extensive, the most salient quick answer is that subjects who had treatment adjustment in the 1st year of the D-02 study had a response rate of 21% whereas those without any adjustment (apart form VNS) had a 41% response rate. Clearly with such data, medication adjustments could not have been of much importance relative to the presence of VNS.

The attempt to cap treatments at 6 (and please note, this meant ATHF validated failures in the current episode only, not over the subjects lifetime) was done because preliminary data in the acute phase of the D0-1 pilot study indicated that patients with a score greater than 6 on ATHF criteria did not do as well. One year and two year data on these same subjects did not maintain this relationship. In hindsight it may simply mean that the greater degree of treatment-resistance requires a longer period of treatment to show effects. The question of why subjects with substantial suicidality are excluded indicates a complete ignorance of the usual standards for conducting clinical trials in depression. This is a standard criteria for any trial in depressed subjects and is done so for reasons of safety. Moreover, for a treatment like VNS with such an apparently slow onset, it would be unethical to undertake a trial in any person with such an unstable and potentially lethal circumstance.

The report states “significant confounding was introduced to the examination of results for the variable of interest when there was concurrent optimization of other treatments that may vary from site to site, clinician to clinician; with this random approach, one cannot be confident of which treatment, or combination of treatments, caused the clinical change.” I have already addressed the concern over concomitant treatment use above. Site to site variances are part and parcel of all multi-site studies, but have been looked at extensively in these studies and found to be relatively minor and to have little to no bearing on the long-term results.

Finally, the argument that major depression and TRD in particular is biologically heterogeneous and, therefore, not amendable to studies of various treatments is specious. Most medical syndromes (hypertension, congestive heart failure, etc.) have multiple etiologies. This is inherent on the definition of a syndrome. To argue that such heterogeneity somehow prevents treatment studies is illogical. That is why additional treatments are desperately needed. The VNS studies followed state of the art methods from the outset. The results provide strong evidence for safety and long-term efficacy for these patients.

I am hopeful that this has clarified the data related to the basis for your review of VNS for patients with Treatment Resistant Depression. In the proper context, one must conclude that VNS offers benefit to patients with TRD and is the only available treatment for these patients for long-term care of their illness. As such, it is imperative that CMS cover this benefit to provide access to these individuals suffering from TRD.

If you have any questions or need further clarification, please do not hesitate to contact me. Thank you for your attention in this matter.

Sincerely yours,

A. John Rush, M.D.
Vice Chair, Department of Clinical Sciences
Professor of Psychiatry
Betty Jo Hay Distinguished Chair in Mental Health
Rosewood Corporation Chair in Biomedical Science
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, Texas 75390-9066
john.rush@utsouthwestern.edu
(214) 648-4832

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As President of NAMI Indianapolis, a local affiliate of the National Alliance on Mental Illness, we frequently encounter individuals who have Treatment Resistant Depression. Because of their disabilty, many of these individuals depend on Medicaid and Medicare to pay for medical expenses. We MUST keep every option open for finding new treatments to relieve symptoms, and help these individuals return to a more productive life-styly.

If there were new treatment options for cancer or heart disease with the same degree of support and efficacy by medical professionals and, would we not be supporting the approval of Medicare to pay for treatment? It appears in your report, that the only parties recommending the Vagus Nerve Stimulation not be approved by Medicare are insurance companies. How long will we allow these companies to drive treatment options?

We strongly recommend that Vagus Nerve Stimulation be approved for coverage by Medicare. The cost effectiveness of helping people return to work and productive lives, will in the long-run, far out-way the intitial cost of treatment. I know there is research that shows this to be fact.

I trust the research will be studied and considered carefully. Cutting public funding for mental health services has historically cost tax payers more in the long run. Treatment Works!! Let provide VNS as an option for individuals who cannot afford private insurance.

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To: Committee on Medicare and Medicaid Services

Re: Proposed Coverage Decision Memorandum for Vagus Nerve Stimulation for Treatment Resistant Depression

Administrative File: CAG-00313R

Dear Committee:

As a clinician-scientist and psychiatrist who devotes his life to the study of the pathophysiology and treatment of individuals suffering with severe mood disorders, it is with great disappointment, surprise, and concern that I read the CMS conclusions re: preliminary decision to not cover Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD). I have been intimately involved in the study of this new and promising treatment, and, in my opinion, failure to reimburse TRD patients for this procedure will lead to needless and significant suffering (by both patients and their families), significant unresolved illness, and tragic deaths (by suicide).

In my review of the “Proposed Decision Memorandum” (CAG-00313R), there are several lines of reasoning that I believe need to be more thoroughly considered. My arguments, more fully outlined in the paragraphs that follow, are summarized by the following points:

1) Mood disorders in general, and depression in specific, are incredibly complex brain disorders involving specific brain regions and a complex interplay of biochemistry, environmental stress, genetics, and neurophysiology. Though, as the reviewers commented there are no “objective” tests for depression, significant sophisticated science exists to support a neuroanatomical/biochemical basis for depression (eg., animal studies, functional and structural neuroimaging studies). The absence of a simple “objective” measure for depression simply reflects the complexity of this disorder and our current limitations to assay it, not the lack of validity/reliability of the construct.

2) Major depressive disorder (MDD), as has been noted by the Surgeon General of the United States and the World Health Organization, is among the leading causes of morbidity in the United States/World.

3) There exists a particularly virulent form of depression, treatment-resistant depression (TRD) that afflicts a small, but significant portion of the population. Though, as the authors of the Proposed Decision Memorandum (CAG-00313R) point out, the field of psychiatry has not yet perfectly defined what represents TRD, any reasonable review of the antidepressant treatment literature would lead one to conclude that there are individuals who have failed numerous adequate dose and duration treatment trials who can be referred to as “treatment resistant”. Recent studies (STAR*D Trial among others) have demonstrated that a significant subset of depressed individuals will fail a series of aggressive and systematic antidepressant treatment trials. Though one could reasonably argue that the United States Food and Drug Administration (FDA) set the threshold “too low” for the indication of VNS for TRD, there clearly exists individuals who would meet a much higher threshold (for example, individuals with histories of failure of 6-7 adequate dose-duration trials of antidepressants/combination strategies, and aggressive pharmarcotherapies and somatic therapies [eg., failure to respond to a monoamine oxidase inhibitor or electroconvulsive therapy]. I would favor a more reasonable “higher threshold” preliminary coverage determination that would allow for this treatment (VNS) in the “sickest of the sick” subpopulation, who, without question, can be agreed upon as treatment resistant. Psychiatry as a field will continue to further define the nature of treatment resistance, but all parties involved can reasonably agree that such an entity (TRD) clearly exists.

4) Given the serious degree of suffering and imminent life-threatening nature of this virulent subform of depression, as well as the absence of effective treatments for TRD, the existing longitudinal treatment and safety data for VNS in TRD is adequate to support the reimbursement of this device/treatment in this subpopulation of the “sickest of the sick”. The absence of other treatments with sustained efficacy requires a “compassionate use” indication, such as used in other conditions (eg., cancer, HIV disease) where limited definitive proven treatments exist in a condition with a potential terminal outcome. Additionally, this treatment (VNS), though invasive, has proven to be safe in over 40,000 epilepsy patients worldwide. As our understanding of treatment selection improves, through genetics, neuroimaging studies, etc., better patient selection will follow. For the short term, however, withholding treatment for “perfect studies” for these individuals is inhumane, discriminatory, and will lead to unnecessary suffering and likely deaths by suicide.

5) My personal experience with the TRD population has lead to several observations:

a) the general medical community has little understanding of the degree of suffering and torment TRD patients experience; one important factor in the FDA’s decision to approve the device for TRD was direct consultation with several life-long sufferers of TRD who had finally achieved remission from suffering with VNS. I suggest the CMS committee interview individuals who suffer from TRD as well as individuals who have responded/not responded to VNS for TRD before making any definitive determinations.

b) TRD takes an enormous toll on these patients and their families: failed treatment after treatment, incapacitation, suicide attempts, and psychiatric hospitalizations occur year after year. Though I have witnessed excellent responses to other forms of treatment (pharmacotherapy and ECT), the sustained efficacy I have personally witnessed with this treatment (5 years of sustained remission in 4 of our 10 subjects) is FAR superior to any treatment for TRD I have ever observed.

6) Functional neuroimaging studies (functional MRI, SPECT, and PET; Chae) including PET studies conducted by a joint St. Louis University- Washington University team in St. Louis (Conway et al., 2006), as well as other groups have demonstrated that acute vagus nerve stimulation leads to activation in regions of the brain known to be associated with depression. Further, preliminary longitudinal data from this same group suggests that brain changes occurring with VNS occur in similar regions. The National Institute of Mental Health has reviewed these data and has approved further, larger scale study of the acute and longitudinal metabolic effects on the brain in TRD.

To further elaborate on these primary arguments:

1) Mood disorders in general, and major depressive disorder (MDD) in specific, are incredibly complex brain disorders involving specific brain regions and a complex interplay of biochemistry, environmental stress, genetics, neuroplasticity, and neurophysiology. Early models of the pathophysiology of MDD emphasized specific neurochemicals and neuropeptides (Fava & Kendler, 2000). More recent MDD models emphasize that depression is not likely due to a single brain region or neurotransmitter system, rather, it is a multi-dimensional, systems-level disorder, affecting discrete, but functionally integrated, pathways (Mayberg 1997b). A detailed discussion of the various models of depression is beyond the scope of this letter (for exhaustive reviews: Davidson et al., 2002, Nestler et al., 2002). Multiple and diverse models for MDD exist. Recent models, emerging from both human and animal studies, emphasize interplay of genetics, temperament, locus of control, and early childhood stress (Kendler 2002; Newport et al., 2002). Other models emphasize the role of neurogenesis and the role that antidepressants/mood stabilizers may play in increasing neuroplasticity and cellular resilience (Duman et al, 2001; Manji et al., 2001).

2) Major depressive disorder (MDD), as has been noted by the Surgeon General of the United States and the World Health Organization, is among the leading causes of morbidity in the United States/world. This point is without debate, depression places an enormous financial burden on the United States and has become a focus of the public health system in the United States as noted by the Surgeon Generals’ statement referenced in the reviewers memorandum. Depression is estimated to effect 18 million people in the United States and 340 million people worldwide. 2/3 of these individuals are women (Greden, 2001; Kessler, 2003).

3) There exists a particularly virulent form of depression, treatment-resistant depression (TRD) that afflicts a small, but significant portion of the population. The authors of the memorandum correctly conclude that there likely exists a need for greater precision in the definition of TRD; however, there can be no reasonable argument TRD doesn’t exist. The literature clearly describes the recurrent nature of depression and the interplay between this recurrence and resistance to treatment.

As noted above, millions of Americans suffer from MDD. Despite numerous treatments, it is estimated that 50% will not respond to an initial pharmacotherapy trial and 30% will not benefit from a series of treatment trials (Hirschfeld et al., 2002). TRD exacts an enormously high toll on treatment resources (Corey-Lisle et al.,2002; Katon et al.,1990). In fact, these studies suggest that the relatively small percentage of patients with TRD place an unusually heavy burden on the overall cost of depression treatment. Also, TRD sufferers have more impairment in the home and workplace (Miller et al., 1998), and they are more likely to commit suicide, and suffer more severe morbidity and greater medical co-morbidity (Thase, 2004).

Clinical staging of TRD: Systems for staging antidepressant (AD) resistance have evolved (Fava & Davidson, 1996, Thase and Rush,1997). Thase and Rush have devised a five stage system to define AD resistance. Based on this model, those who fail to respond to treatment with a single AD (Stage 1) have an estimated 30-50% chance of responding to a second AD or psychotherapy (Thase and Rush, 1997). Climbing the stages, likelihood of response diminishes more rapidly. In fact, the “differential step” in the staging system occurs at the Stage II point: failure to sequentially respond to two of the newer ADs predicts significantly greater resistance to a third newer AD (Hirschfeld et al., 2002).

Limited proven effective treatment options for TRD create the need for future outcomes research: A recent review (Thase, 2004) suggests only three systematically-determined treatments are effective in MDD after two sequential ineffective AD trials: lithium augmentation, monoamine oxidase inhibitors, and electroconvulsive therapy (ECT).

To prospectively address the issue of subsequent treatment failures, the National Institute of Mental Health sponsored the largest, sequential AD trial (Systematic Treatment of Alternatives to Relieve Depression [STAR*D]) to systematically assess AD strategies. Stages 1 and 2 of the STAR*D trial suggested approximately 48% of patients have failed to remit after a sequence of AD trials over 26 weeks (Rush et al., 2006; Trivedi et al, 2006). During STAR*D Stages 3 and 4 (Fava et al., 2006; McGrath et al., 2006) ~40% of the initially depressed group had not remitted. Finally, after step 4 of STAR*D, ~36% had still not remitted. Hence, following 4 steps of systematized AD treatments, the STAR*D trial concludes that a large and significant population (approximately 36%) of depressed patients do NOT achieve remission and would constitute treatment- resistant depression (TRD).

Electroconvulsive therapy (ECT) has a well- established safety/efficacy history and is considered a mainstay of treatment for TRD: however, it has significant limitations. First, though efficacious for severe, acute depression, recent studies suggest ECT has a dismal record in maintaining TRD response: 64% of TRD patients responding to ECT relapse 12 months later (whereas only 32% of non-TRD relapse in one year; Sackeim et al.,1990). Further, ECT has significant short term impairments: long recovery time (missed work, etc.), transient memory deficits (both retrograde and anterograde) (Squire, 1977). Hence, our current knowledge strongly suggest that: a) there is a decremental likelihood of response to treatment, i.e., failure to respond to a each antidepressant treatment decreases the likelihood of response to the next treatment; b) there is a significant subset of individuals who do not respond to an aggressive series of treatments (as defined by the STAR*D trial); c) the “gold standard” of treatment for TRD, electroconvulsive therapy, does not have lasting efficacy in TRD., i.e., ~64% of patients relapse into depression after one year. Clearly, our current therapies do not adequately address this severe and deadly condition.

4) Given the serious degree of suffering and imminent life-threatening nature of this virulent subform of depression, as well as the absence of effective treatments for TRD, the existing longitudinal treatment and safety data for VNS in TRD is adequate to support the reimbursement of this device/treatment in this subpopulation of the “sickest of the sick”. The absence of other treatments with sustained efficacy requires a “compassionate use” indication such as used in other conditions (eg., cancer, HIV disease) where limited definitive proven treatments exist in a condition with a potential terminal outcome. Additionally, this treatment (VNS), though invasive, has proven to be safe in over 40,000 epilepsy patients worldwide. As noted under point #3, the existing data support the premise that what has long been considered the “gold standard” of treatment for TRD, electroconvulsive treatment, has no significant lasting efficacy in 2/3’s of those with TRD. Though the data currently in existence for the efficacy of VNS in TRD is less than definitive, there is a sufficient compelling evidence that the effects are NOT secondary to normal “waxing and waning of symptoms” or placebo effects, as is suggested by the authors of the memorandum. I concur with the concerns of the reviewers re: the potential of placebo effects; however, the literature cited regarding depression studies and placebo effects is relevant to mild-moderate depression: it is well- established that the antidepressant placebo effects decrease with severity of the depressive condition, i.e., historically TRD has a much, much lower placebo rate and placebo effects in TRD are not usually sustained, whereas the existing literature supports those responding to VNS stay well—see next paragraph (Rush and Thase, 1995; Quitkin et al, 1987; Sackeim et al., 2000).

Evidence of the sustainability of the response of VNS has been tracked from BOTH the D01 and D02 study at one and two years. At one year followup of the pilot D01 trial (Marangell et al., 2002) demonstrated not only sustained response and remission rates, but even greater response and remission rates (44% response, 27% remission). Even more compelling, recently published 2 year data from this study (Nahas et al., 2005) continues to demonstrate sustained response and remission rates (42% and 22%, respectively). Most recently, Sackeim et al. (provided courtesy of Dr. Harold Sackeim, 2006) have summarized sustained efficacy data for the pivotal trial: approximately 70% of the responders in the pivotal trial at 12 months continue to respond at 24 months.

The treatment as usual (TAU) trial (D-04) which was run in parallel to the observational study (D-02) demonstrated active treatment to be statistically much more efficacious on the D-04 primary measure (IDS-SR; the IDS-SR was a secondary measure for the pivotal trial [D-02]) for both response and remission from MDD. I disagree with the memorandum authors’ observation that significant efforts to match populations did not occur in these two parallel studies: on a plethora of variables (age, duration of depression, number of failed treatment trials, severity of depression) matching was near perfect. In fact, no other studies of TRD on this scale, with this effort of demographic matching, exists in the literature.

In conclusion, the sustainability of the response, the recognized smaller placebo effects typically observed in TRD studies, the statistically powerful difference in efficacy outcomes between TAU and active treatment (VNS), all argue for this treatment, especially in individuals who have no other viable treatment options and have a deadly, potentially terminal illness. To await the “perfect trial” when an existing treatment with strongly supportive efficacy and safety data exists is not ethical in the writer’s opinion.

5) My personal experience with the TRD population and VNS treatment for this population has lead to several observations:

a) the general medical community has little understanding of the degree of suffering and torment TRD patients experience; one important factor in the FDA’s decision to approve the device for TRD was direct consultation with several life-long sufferers of TRD who had finally achieved remission from suffering with VNS. I would strongly suggest that the CMS committee consider interviewing a set of individuals who suffer from TRD, both those who have received VNS and responded/failed to respond, as well as those who have suffered from TRD for literally their entire lives. Most non-psychiatrist physicians rarely come into contact with this severity of depression and have little exposure to the devastating life impact it has on people’s lives. All of the subjects at our site (4 of 10) who remitted would be willing to appear before the Committee.

b) TRD takes an enormous toll on these patients and their families: failed treatment after treatment, incapacitation, suicide attempts, and psychiatric hospitalizations occur year after year. Though I have witnessed excellent responses to other forms of treatment (pharmacotherapy and ECT), the sustained efficacy I have personally witnessed with this treatment (5 years of sustained remission in 4 of our 10 subjects) is FAR superior to any treatment for TRD I have ever observed. Being from the “Show-Me” state, I am a skeptic by nature. I know the natural course of TRD, and when subjects in the clinical trial began to respond and the response lasted, and lasted for year after year, I slowly became a “true believer”. So much so, that I have staked my research career (NIMH K-award recently awarded for me to study functional neuroimaging of VNS in TRD). Many of these individuals have spent the greater portion of their lives incapacitated by depression. Seeing patients respond to this treatment has been the most rewarding experience of my clinical career. Without exception, all of our remitting subjects have become powerful advocates for VNS in TRD, because their biographies are “living proof” of the efficacy of the treatment. In fact, on one of our subjects, Charles Donovan, has appeared on national television and has written a book, “Out of the Black Hole” to describe his sustained response (5 years running) to VNS.

6) Functional neuroimaging studies (functional MRI, SPECT, and PET; Chae et al., 2003) including PET studies conducted by a joint St. Louis University-Washington University team in St. Louis (Conway et al., 2006), as well as other groups have demonstrated that acute vagus nerve stimulation leads to activation in regions of the brain known to be associated with depression. Further, preliminary longitudinal data from this same group suggests that brain changes occurring with VNS occur in similar regions. The National Institute of Mental Health has reviewed these data and has approved further, larger scale study of the acute and longitudinal metabolic effects on the brain in TRD.

Acute VNS activation in TRD using [15O]H2O PET (Figure 1). The manuscript for this study was accepted for publication in November 2005 (Conway et al., 2006) in Psychiatry Research Neuroimaging. The purpose of this pilot study was to identify changes in rCBF in response to acute VNS in subjects with TRD. [15O]H2O PET was used to detect brain regions of increased and decreased rCBF in response to acute VNS. To do this, four subjects with TRD were enrolled. Prior to subjects being initiated on sustained VNS, they received 90-second [15O]H2O PET scans in an off-on sequence, (two scans with VNS de- activated and two with VNS activated), to coincide with an intravenous bolus injection of 50 mCi of [15O]H2O. PET images were aligned, normalized for global uptake, and resampled to standard atlas space. Statistical t-images were then calculated to evaluate VNS-induced changes (to determine regions demonstrating greater or less rCBF as a result of acute VNS activation). Additionally, HRSD24 scores were obtained at baseline and after 3 and 9 months of VNS therapy.

Statistically significant, VNS-induced increases in rCBF were found in 12 regions and decreases in 9 regions (please see t-statistical transverse MRI-overlayed images [Figure 1 below]). Key regions undergoing increased rCBF included: inferior frontal gyrus, posterior orbital gyrus, medial orbital gyrus, anterior cingulate, putamen, superior frontal gyrus, cerebellar body, fusiform gyrus, and precentral gyrus. Areas that underwent decreased rCBF included: inferior parietal lobule, superior parietal lobule, anterior tip of the inferior temporal gyrus, medial temporal gyrus, post central gyrus, post central gyrus, precentral gyrus, and the precuneus. (The exact regions, including Brodman’s areas designations, associated t-scores, and Talairach Atlas coordinates can be found in the manuscript in the Appendix of this application). Noteworthy findings include:

I. Acute VNS in subjects with TRD caused significant rCBF changes in specific brain regions (orbitofrontal cortex, anterior cingulate cortex, superior and middle frontal cortex, anterior temporal lobe) previously identified with metabolic abnormalities in mood disorders. These regions are known to be along the “upstream” vagus afferent pathway and have been consistently demonstrated abnormal activity in previous neuroimaging studies of depression (Brody 2001; Ebert 1994; Kimbrell 2002; Mayberg 1997). II. Areas undergoing increased rCBF and decreased rCBF support brain models of corticolimbic network reciprocity. Of the 10 cortical regions of increased rCBF (activation) found here, 7 were frontal or prefrontal. Of the 12 cortical areas with decreased rCBF only one (8%) was frontal (pre-central gyrus) and there were no prefrontal regions undergoing decreased rCBF. This pattern coincides well with Mayberg’s cortico-limbic depression model, which postulates an imbalance of limbic-frontal circuitry characterized by hypo-metabolism in the prefrontal region and hyper-metabolism in the limbic region (Mayberg 1997a, 2003). Limitations of this study include the small sample size, which limited the statistical power of the analysis and generalizability/stability of the results, including the inability to correlate HRSD24 with rCBF changes. Structural MRI images, which would allow more precise localization of rCBF changes, were not obtained.

Longitudinal Effects of VNS on Regional Brain Metabolism in TRD:
Finally, preliminary evidence (presented at the 2006 Meeting of the Society for Biological Psychiatry; Conway et al., 2006; Figure 2) from Fluourodeoxy-glucose PET imaging of subjects with TRD receiving VNS (at intervals 3 months, 12 months, and 24 months) suggest several findings:

1) Subacute changes (3 mos.) are markedly different, both in direction (considerably more deactivation at 24 months than 3 months) and degree (more areas of deactivation at 24 months) As noted above, this observation is consistent with the premise that VNS acts via a slow evolving change in brain activity.

2) The Summed Average Patient at 24 months demonstrated significant deactivation of the prefrontal regions, especially the dorsolateral prefrontal cortex, previously identified to be critical in depression.

Our current, larger N study will focus on attempting to find neuroimaging “markers” that would, a priori, predict a response to VNS. Further, we will be attempting to specifically correlate regional brain metabolic change with treatment outcome.

Figure 1. (N=4)
t-statistical mapping of significant (t =5) rCBF increases (red to yellow) and decreases (green to blue) induced by VNS in four TRD subjects. The rows are axial images with 6mm spacing, arranged from superior to inferior. Subjects left is image left.

Figure 2: Regional Metabolic Deactivations Occurring at Different Time Intervals of Exposure to VNS in TRD

FDG 3-months VNS: decreased activations

FDG 24-month VNS: decreased activations

In conclusion, I firmly believe that it is critical that CMS reconsider their preliminary conclusions and make VNS available for the “sickest of the sick”. My recommendation at this stage of our knowledge of VNS in TRD, would be make the “threshold” higher than has been established by the FDA and make this treatment available on a “compassionate use” basis. Perhaps increasing the treatment trials to 6 and making a trial of either ECT or a monoamine oxidase inhibitor as essential components of their treatment failures.

I would be more than happy to be confer directly with members of CMS to further discuss issues related to VNS in TRD. As indicated above, several subjects at our site who have responded well or not-as-well to VNS have indicated they also would be willing to speak to CMS.

Thanks for your serious consideration of these matters,

Sincerely,

Disclosure: Dr. Conway has received honoraria for lecturing on depression and VNS as well as research funding by the maker of the VNS stimulator, Cyberonics.

REFERENCES

Brody AL, Saxena S, Mandelkern MA, et al.: Brain metabolic changes associated with symptom factor improvement in major depressive disorder. Biol Psychiatry 2001;50(3):171-178.

Chae JH, Nahas Z, Lomarev M, et al.: A review of functional neuroimaging studies of vagus nerve stimulation (VNS). J Psychiatr Res 2003;37 (6):443-455.

Conway CR, Sheline YI, Chibnall JT, George MS, Fletcher JW, Mintun MA. Cerebral Blood Flow Changes during Acute Vagus Nerve Stimulation for Depression. Psychiatry Research: Neuroimaging, 2006;146:179-184.

Corey-Lisle PK, Birnbaum HG, Greenberg PE, et al.: Identification of a claims data "signature" and economic consequences for treatment- resistant depression. J Clin Psychiatry. 2002 63 (8):717-26.

Davidson RJ, Lewis DA, Alloy LB, et al.: Neural and behavioral substrates of mood and mood regulation. Biol Psychiatry 2002;52(6):478-502.

Duman RS, Nakagawa S, Malberg J.: Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 2001;25(6):836-844.

Ebert D, Feistel H, Barocka A, et al.: Increased limbic blood flow and total sleep deprivation in major depression with melancholia. Psychiatry Res 1994;55(2):101-109.

Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin N Am1996;9(2):179-200.

Fava M, Kendler KS. Major depressive disorder. Neuron 2000;28:335-341.

Fava M, Rush AJ, Wisniewski SR, et al., A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report. In Submission.

Greden JF. J Clin Psychiatry. 2001;62(suppl 22):5-9.

Hirschfeld RM, Montgomery SA, Aguglia E, et al.: Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry 2002 63 (9):826-837.

Katon W, Von Korff M, Lin E, et al.: Distressed high utilizers of medical care. DSM-III-R diagnoses and treatment needs. Gen Hosp Psychiatry 1990 12(6):355-362.

Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in women. Am J Psychiatry 2002;159 (7):1133-1145.

Kessler RC, et al. JAMA. 2003;289:3095-3105.

Kimbrell TA, Ketter TA, George MS, et al.: Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol Psychiatry 2002; 51(3):237-252.

Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nature Medicine 2001;7(5):541-547.

Marangell LB, Rush AJ, George MS, et al.: Vagus nerve stimulation (VNS) for depressive episodes: one year outcomes. Biol Psychiatry 2002;51:280- 287.

Mayberg HS: Limbic-Cortical Dysregulation: A Proposed Model of Depression. J Neuropsych Clin Neurosci 1997a;9:471-481.

Mayberg HS, Brannan SK, Mahurin RK, et al.: Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997b;8(4):1057-1061.

Mayberg HS: Modulating dysfunctional limbic- cortical circuits in depression: towards a development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 2003; 65:193-207.

McGrath PJ, Stewart JW, Fava M, et al.: A Comparison of Tranylcypromine to the Combination of Venlafaxine-XR Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report. In Submission.

Miller IW. Keitner GI. Schatzberg AF, et al.: The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry. 1998 59(11):608-619.

Nahas Z, Marangell LB, Husain MM, et al.: Two- year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry 2005;66:1097-1104.

Nestler EJ, Gould E, Manji H, et al.: Preclinical models: status of basic research in depression. Biol Psychiatry 2002;52(6):503-528.

Newport DJ, Stowe ZN, Nemeroff CB. Parental depression: animal models of an adverse life event. Am J Psychiatry 2002;159(8):1265-1283.

Quitkin FM, et al. Arch Gen Psychiatry. 1987;44:259-264.

Rush AJ, Trivedi MH, Wisniewski SR, et al.: Buproprion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression. N Engl J Med 2006; 354(12):1231-1242.

Sackeim HA, Prudic J, Devanand DP, et al.: The impact of medication resistance and continuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. J Clinical Psychopharm. 1990;10(2):96-104.

Sackeim HA, et al. Arch Gen Psychiatry. 2000;57:425-434.

Squire LR. ECT and memory loss. Am J Psychiatry 1977;134:997-1001.

Thase ME, Rush AJ. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press, Ltd.; 1995:1081-1097.

Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58 Suppl 13:23-29.

Thase ME. Therapeutic alternatives for difficult- to-treat depression: a narrative review of the state of the evidence. CNS Spectrums. 2004;9 (11):808-16, 818-821.

NOTE: I have also sent this message as an attachment because the PET image data we sent would not convert to this format thanks, CC

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Greetings,Medicare patients have benefits that cover organ transplants. Why can't psychiatric patients be covered for this life saving treatment? How can a United States program be a role model for discrimination against the mentally ill? Below are comments I made on the subject of mental health parity for the mentally ill at a recent Congressional hearing:Parity for Mental Health Care: Ethical & Economical[1]Robert C Bransfield, MD, DFAPA

“We are facing a moral crisis as a country and as a people…Those who do nothing are inviting shame as well as violence. Those who act boldly are recognizing right as well as reality.” (JFK)

"I am not going to balance the budget on the backs of the most vulnerable. While this budget stands up for fiscal responsibility and honesty, it also stands up for those who may not be able to stand up for themselves and helps those who need it most." (Governor Codey)

As a member of the American Psychiatric Association Work Group on Parity, Work Group on Access to Care, Managed Care Committee and the New Jersey Psychiatric Association Council, today I speak on behalf of our patients to address the ethical and economical value of mental health parity.

The American mental health system is a good news-bad news story. The good news is there is advanced diagnostic and treatment capability to effectively and cost effectively treat illness that afflict the most complex structure in the known universe—the human brain. The bad news is the average working person with the common insurance policies often lacks access to this capability as a result of inequities and deficiencies of mental health coverage and misguided cost containment in 98% of insurance plans. In New Jersey patients with anorexia nervosa and other biologically based mental illnesses are denied treatment for life threatening conditions because insurance companies argue that coverage for this and other conditions may not be required under current New Jersey parity legislation. Parity or equalization of mental health benefits is the only ethical and economically sound approach to correct this serious failure in our health care system.

This is an ethical and human rights issue. Adherence to ethics and the recognition of human rights has not always benefited the short term goals of special interest groups. Insurance company discrimination against the mentally ill is similar to other forms of discrimination based upon race, religion, sex and ethnic background. Discrimination against diseases of the brain, discrimination against those afflicted by brain diseases is unethical and a violation of fundamental human rights. This discrimination is implemented and concealed by the use of managed care, pharmacy benefit management plans, carve-out programs and phantom provider networks. We cannot advance special interests and support excessive insurance company profits and cost shifting to government programs by allowing unequal benefits for the mentally ill.

The human resource of creativity and productivity are the most valuable American assets and are critical in our society and economy. Higher levels of mental fitness and resilience correlate not only with happiness, but with creativity and productivity as well. Maintaining parity for mental health care protects and preserves this vital human resource. Conversely, inadequately treated mental illness correlates with diminished productivity, increased physical illness, increased risk of substance abuse, greater social discord, violence and pain and suffering. Mental health and physical health are assets that need to be maintained and protected.

Diseases and disorders of the central nervous system (CNS) cause more direct (health care costs) and indirect costs (e.g. pre-absenteeism, absenteeism, premature retirement, lost productivity and caretaker burden) than any other disease category, yet the treatment of these diseases receive less resources than other conditions. Mental disorders; substance abuse; degenerative diseases of the CNS; and psychiatric components to behavioral disorders and general medical illnesses which increase the severity of many general medical illnesses, cause psychosomatic illness, reduce compliance rates of medical treatments and increase the need for many diagnostic procedures all contributors to a massive burden to our society. The effect of psychiatric conditions upon increasing general medical illnesses through indirect costs has never been calculated and is probably hundreds of billions per year and is probably greater than any other cost. Some statistics on the costs of mental illness are missing and some are over 15 years old and vastly underestimate 2007 costs and include:

$279 billion for alcoholism (1998)[i] $172 billion for drug abuse (1995)[ii] [iii]$100 billion for Alzheimer’s (2003)[iv] $108 billion for insomnia (1994)[v] $83 billion for depression (2000)[vi] $77 billion for attention deficit/hyperactivity disorder (2004)[vii] $48 billion for brain injury brain injury $48 billion[viii] $45 billion for bipolar disorder (1990)[ix] $42 billion for anxiety (1990)[x] $30 billion for developmental disabilities[xi] $30 billion for lost productivity from schizophrenia from lost productivity (2002)[xii] $1.014 trillion total

For other conditions which often have a psychiatric component (approx 1/3):

$2.1 trillion for medical treatment costs (2006 projected)[xiii]$425 billion from violence (1998)[xiv]$145 billion from work accidents (2001)[xv]$102 billion from obesity (1999) [xvi]$100 billion from pain[xvii] $73 billion for cigarette smoking (1998)[xviii] $35 billion from work related violence (1995)[xix]$2.980 trillion total x 1/3 =$.993 + $1.014=$2 trillion conservative yearly cost of mental illness

There have been many objective studies and all demonstrate increased total costs as a result of obstructing access to psychiatric care and psychotropic medications and reduced costs from improved access to psychiatric care and psychiatric medications.[xx] [xxi] [xxii] [xxiii] [xxiv] [xxv] [xxvi] [xxvii] [xxviii] [xxix] [xxx] [xxxi] [xxxii] [xxxiii] [xxxiv] [xxxv] [xxxvi] [xxxvii] [xxxviii] [xxxix] [xl] [xli] [xlii] [xliii] [xliv] For every dollar spent on substance abuse treatment taxpayers saved 7 dollars in future costs.[xlv]

Two examples of the value of parity are Pitney Bowes and Merrill Lynch. Pitney Bowes reported that investing in employee mental health assessment and treatment programs reduced absence, increased productivity and helped address overall health care and disability costs.[xlvi] Merrill Lynch reported that by removing restrictions on mental health and psychotropic medications, the firm’s total health care costs after adjusting for inflation was reduced by 25% per employee. [xlvii]

There are many more effective opportunities to curtail health care costs other than restricting mental health benefits. Although two trillion dollars are consumed by our health care system per year, a Boston University study demonstrated only half of health care spending is actually on health care. The other half is wasted on unnecessary spending, in particular administrative costs and profit in the insurance company.[xlviii]

Parity must also apply to Medicare. Under current Medicare rules, Medicare pays 80 percent of the cost of a doctor treating a physical ailment and patients pay 20 percent. But mental health patients must pay half the cost for therapy treatments out of pocket because Medicare only covers 50 percent. Parity of mental health care is also needed for returning veterans and their families.

The legislators who hear this message have an opportunity to make a difference. Implementing the New Jersey Senate parity bill (A2512) and the Patrick Kennedy-Ramstad House parity bill that will provide a floor for minimal parity requirements can help to restore ethics and save hundreds of billions in many indirect health care and other costs. Although employer mandated health insurance coverage is unfair, it is also unfair to partially evade this responsibility by discrimination against the mentally ill and other bad faith insurance practices that are inappropriately shielded by ERISA. Healthcare insurance must be clearly understandable, transparent, ethical and accountable. America is the world leader and the major exporter of health care technology, but access to mental health care is currently challenging. As a world leader, we are a role model for others. The mentally ill and handicapped people who wander in our streets and fill our jails are constant reminders of the inadequacies of our current system and negatively portray our human values. Parity for mental health care is an opportunity for us to be a positive role model for access to humane care.

“The moral test of a government is how it treats those who are in the dawn of their life, the children; those who are in the twilight of life, the aged; and those who are in the shadows of life; the sick, the needy and the handicapped.” (Hubert Humphrey)

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March 6, 2007

Centers for Medicare and Medicaid Services (CMS)
Att: Beverly A. Lofton, MHA
Ref: NCA for Vagus Nerve Stimulation for Treatment of Resistant Depression (TRD) (CAG- 00313R)
C1-09-06
7500 Security Blvd.
Baltimore, MD 21244

Dear Ms. Lofton:

I am once again writing in support of Vagus Nerve Stimulation Therapy for treatment resistant depression. CMS’s proposed decision memo for VNS for TRD is very disappointing. I was hesitant to write again, as it is clear that your group did not listen to my opinion, the opinion of my specialty organization (the American Psychiatric Association) and the opinions of hundreds of my fellow psychiatrists: the people that see, and help the millions of Americans who suffer from the horrible disease of depression. I did decide to write again as it is clear from the memo and its inaccuracies, that CMS really does need to hear more from those who are the experts in refractory depression.

Further, you gave no weight to the comments of those who are suffering from the disease, either in themselves or a family member. This is very unfortunate, because these collectively are the very people who know and can describe treatment resistant depression and have a vested interest in its treatment. Unfortunately, you did seem to listen to biased insurance companies and other concerns- whose vested interest is to save money, not lives- and their flawed “TEC” reports.

I would like to correct some of the assumptions made in the coverage decision that I believe played a part in the coverage decision in this letter as well as describe some of my experiences that I have had with VNS, to help elucidate what a mistake it would be to let this coverage decision stand.

Your background documentation seemed to be missing that much of the most important aspects of the diagnosis and treatment of depression are clinically and not research based. Due to the nature of the disease, objective signs are not reliable. This proposed coverage determination portrayed a shocking lack of concern for your wards and the suffering that they are enduring and of a clear lack of expertise and understanding of refractory depression in those writing the opinion.

This ruling epitomizes the stigma that I battle with my patients everyday and if it goes through it would continue to perpetuate the bias that psychiatric patients deal with everyday by sending the message that their disease is not as important or worthy of treatment as those with epilepsy, another brain disease, as you will cover VNS for one group and not the other with an imperceptible difference in the evidence base. To impute that there is sufficient evidence for VNS in epilepsy and not depression is perpetuating a falsehood. A reasonable assumption could be that to cover epilepsy and not depression with a similar evidence base (if not weaker in epilepsy) is a bias against mental illness, something that I unfortunately see every day in payers of all types.

Many of the assertions in your background documentation were not a true statement of the current state of psychiatric knowledge or standard of care. To say that we are unaware of the specific locus of pathology for depression and to use that to question the clinical construct of treatment resistant depression, portrays a frightening lack of understanding of this admittedly very complex disease, particularly for a group that yields the power to affect the practice of those of us who do understand it. It also seems to say “if we can’t see it, its not real”, which is at the core of discrimination against psychiatric disease. There very well may not be one specific area that is malfunctioning in depression. Depression is much more complex than that. To somehow question the scientific validity of the construct of major depressive disorder because we have not located the “place” where it occurs is being too concrete about such a complex disorder. Depression is very subjective and does not lend itself to easy measurement and it thus is one of the most difficult disorders to conceptualize and define. Depression and treatment resistant depression are clinical entities that we know exist and treat and manage on a daily basis. We are able to reliably define and measure them to quite an impressive degree, considering how complex they are. The HAMD and the IDS are both widely used and reliable tools used in research and clinical practice to define, measure and follow treatment responses in depression. HAMD and IDS are standard scales that are well established in psychiatry. The IDS in the VNS acute treatment, placebo controlled trial was statistically significant. Many of the treatments that CMS pays for, especially psychotropics have used these measures in their pivotal trials and they were not questioned at that time. Questioning them, and the construct of resistant depression at this time seems disingenuous at best.

Also, to say that depression, once identified “can almost always be treated successfully” is not true. It certainly is not true in my practice or that of my colleagues. To make such a statement is now well known to be false as seen by the STAR-D trial where only 67% of patients could be treated to remission, even when using a very aggressive treatment paradigm. The difference between 67% and “almost always” is a large chasm in which many people- mothers, fathers, sons, daughters, sisters, brothers- fall. This is the most salient reason why VNS must be available to your wards, to have an opportunity to treat those that our current treatments cannot. There are many patients out there in which our current treatments do not work. VNS should be available for those patients.

I have seen VNS help these refractory patients. Apart from my participation in the current VNS trial, I have managed over twenty patients that have been implanted with VNS for TRD. While it certainly has not treated every patient to remission, I have seen it as a valuable addition to our treatment armamentarium. Patients have agreed. I have seen many patients have their depressions improve greatly after VNS was added to their regiment. I have seen in my own practice, patients who have needed electroconvulsive therapy weekly for years, no longer need ECT. Whether that lasts has yet to be seen, but saving these patients six to nine months worth of weekly ECT treatments is miraculous. These are patients who have hit rock bottom and have no other choices. My similar patients without VNS are prone to have suicide attempts. I have had none of my patients with VNS (over 20) have any suicide attempts, and this is a very high risk population. I have patients who have been implanted for over a year and this has remained true. VNS is helping these people stay alive, feel better and participate in life. Clearly, VNS is a new treatment. It is a new modality. It is a new way of looking at an old problem. Its evidence base is growing, but I have absolutely seen its benefit in my clinical practice.

With this proposed coverage decision as it stands, you are taking an important tool out of my hands and affecting the practice of psychiatry in this country tremendously. This is the government dictating how I practice medicine. I will not be able to use VNS in Medicare patients. It would be a shame, as these are the patients whose lives have been catastrophically affected by mental illness to the point that they are disabled. These should be the people that are being treated with this heroic treatment. The poor, elderly and disabled wards of Medicare will be unable to get a treatment that their peers with private insurance are able to.

Clearly, CMS does not understand this complex disease, and that’s ok. Most physicians do not. That does not mean that they should not cover the treatment. What this means is that they should refer to the specialists that have a clearer understanding of this disease and their patients when considering coverage of this treatment modality. I encourage CMS to look at all 1800 of the letters sent in by psychiatrists, patients and their families that they previously disregarded. They are the true experts. The clear consensus of the opinions of the experts is to allow VNS to be covered. It is the right thing to do, medically and morally. Please do not turn your back on these patients who rely on Medicare to take care of them.

Please reverse this coverage determination/ discrimination.

Sincerely,

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I appreciate the opportunity to respond to the CMS proposed policy of non-coverage for Vagus Nerve Stimulation (VNS) as a treatment choice for treatment resistant depression (TRD).

My comments are based on my experience as a psychiatrist, who has a dedicated career in the research and treatment of TRD. I have published hundreds of studies/articles in peer-reviewed journals in the area of TRD, and have been a primary investigator in over 100 studies in the diagnosis and management of affective disorders (funded by federal resources, industry fubding, and philanthropic funding). I have participated in many studies that have established the validity and reliability of outcomes to assess remission, response, and recovery, in affective disorders, including TRD. Most important, I spend most of my time seven days a week, seeing patients and their significant others who are impacted by TRD. TRD is a devasting disease, and one which has been vastly understudied, until the recent decade. Despite the fact that TRD is among the most disabling diseases in medicine, it remains among the most treatable illnesses in medicine; as long as the experts in our field have treatments available to provide remission and recovery. My passion to see patients who suffer with this illness is reinforced by the individuals who have finally experienced symptomatic releif, and have been able to return to a level of function occupationally, socially, and individually contributes back to our society...helping to remove the primitive stigma of depression percieved by too many people in our society.

I was involved in the VNS D-02 trial, and enrolled 10 patients; and have subsequently implanted 36 patients since the FDA approval of VNS for TRD. Of these patients, my outcomes have paralled those of the original D-02 data, and have documented sustained remissions beyond 4 years. Among this population, 9 patients who came in on disability secondary to their TRD are working full-time jobs, and I can elaborate on the other patients who have had significant changes in in their life, and those of significant others, as a result of VNS. Compared to my patients who have 'treatment as usual' without VNS (including patients who have very aggressive treatments including acute/maintenance ECT, combination medications (average 7.8 psychotropics), psychotherapy, and cingulatomy; my patients with VNS have demonstated the most robust, SUSTAINED outcomes (symptomatic and functional). the MOST impressive outcome of my experience with VNS has been the sustained outcomes at sustaining remissions for years...we should expect nothing less, and I would support most legal pursuits that would deny a person with TRD the chance to get such a treatment, who had a 'preventable' outcome such as suicide, because they were denied the chance to recieve the treatment for the reasons outlined in the CMS policy. No different from cancer, treatment resistant epilepsy, or potentially fatal infections. Such a policy, clearly discrimates depression from other medical illnesses, despite the fact it remains among the most treatable illnesses in medicine.

Up to this point in my response, I provide my own personal experience as a clinician and research psychiatrist. I appreciate the chance to comment on the 'misperceptions' of the individuals who provided comments that supported the 'non-coverage' policy of VNS for TRD. I refer these reviewers to the multitude of literaure that supports the definition of TRD, the impact of inadaquetly diagnosis and treatment of TRD, and the grossly, obvious lack of understanding of the symptomatic and functional outcomes used to measure depression outcomes(including those used in the D-01, D-02, and D-04 studies). I do not mean to be judgemental to these reviewers, but, they will inevitably need to support their knowledge, experience, and explainations as to why these same outcomes that are accepted as outcomes for many FDA-approved treatments for depression (including TRD); I assume that CMS provides legal representation for those who have made public comment resulting in the proposed CMS non- coverage policy. As a clinician who takes great pride in supporting the expected outcomes for my patients with TRD, support clinicians who attempt a similar effort to help their patients with TRD (who are often brought to malpractice for 'expected' poor outcomes like suicide, in TRD patients who are denied access to potentially effective treatment like TRD), and work with advocacy and political groups who advocate the chance to recieve a treatment that is otherwise denied because of cost/availabilty (based upon unjustified responses by reviews as described above)....I ask that you re-evaluate your previous decision.

Several weeks ago, I had to watch a patient suffer a permanant physical disablity, that has been attributed to his family trying to come up with the costs for VNS. He had suffered years of recurring depressions, and despite his illness, worked for 37 years to support his family and community; he had breif remssions, and was an ideal person for VNS. He did not want to jeapordize his family's security, by paying 'out of pocket'; in the last 4 years, he was on social security disability, and medicare, something he articulated shame. I have little doubt from my experience that he would have gained benefit from VNS, and return to his previous passions, including work and his family. Unfortunately, he will not be able to ever know that hope, to experience the relief of his symptoms, that gave him less and less frequent breaks from his suffering. Along with his family, I share in this loss every day.

I request that you reconsider your decsion, and even suggest asking if there are ways to make this treatment available to the 'appropriate' populations' who can benefit, as many of my own patients. The long-term data, based upon valid and reliable data, spaeks for itself, and as a clinician, who continues to do research in this area, I have to expalin to too many informed patients and their famlies, the 'unexplainable' reasons why they are denied a chance to releive their suffering, in the time of medicine when innovative approaches like VNS, are proven effective but unavailable.

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Dear Sirs,
VNS has been definitively demonstrated to be an effective alternative for treatment refractory depression(TRD). It has been usefull in restoring fuvtionality to life not otherwise available. While certainly not a first line treatment option, it should be easily available for those appropriate patients with real TRD. Moreover, placing unnecessary hurdles for already traumatized patients to negotiate is simply cruel. Medicare allows emerging,and very expensive,options for treatment refractory Cancer, even if the result is to extend the patient's life for a few months. Why not apply the same policy to treatment for TRD which offers efficacy over years and decades of a more funtional lifetime?
Sincerely,
Allen Chroman MD DFAPA

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As a practicing psychiatrist, board certified in adult and geriatric psychiatry, I am writing to urge the CMS panel to authorize payment and acknowledge the effectiveness of vagal nerve stimulation. In my practice, I am increasingly presented with patients with a form of depression that has been persistent, unremitting and severely disabling. Diagnosed, with treatment resistant depression, these patients have typically been treated with as many as ten different antidepressant, mood stabilizing, anxiolytic and antipsychotic agents. Most have resorted to electroconvulsive therapy as a last ditch attempt to endure their symptoms. Most often, they are on a combination of medications that may offer them little relief, at great expense, and try forms of counseling which provides, at best, a form of support and connection from this isolating and debilitating disorder. It is a well established fact that these patients utilize more than their allotted mental health benefits and do so without extensive periods of relief. Their absences from work, place further financial burden on their families and to society. Literature shows that patients with treatment resistant depression utilize greater than $41000 per year in medical services. Again, I treat these people in my practice. Treatment resistant depression is not theoretical. It is real, serious and its disabling effects on peoples lives warrant your authorization of any new, and promising form of treatment. I have watched two such patients experience profound improvement with VNS. They are both now able to take only two medications per day and are managed with routine outpatient follow-up appointments. More importantly, both patients report a new felt sense of well-being since implantation with VNS. Neither of these individuals was able to achieve symptom relief before despite more that 8 years of treatment. In contrast, I have three patients who have so far been denied access to VNS treatment due to denial by insurance companies which follow your lead. These patients are clinging to the hope that VNS will afford them a future without despair. I find it unfathomable to think that a treatment that has been FDA approved as effective, could be denied to these patients. VNS has been approved for treatment resistant seizures despite less compelling studies. New treatments for cancer and HIV are approved in a more expedited fashion than VNS. It seems that once again, psychiatric disorders are not being given the same consideration as other medical matters.The mentally ill, often unable to advocate for themselves, are once again being denied parity. With capitated benefits they are already treated with limited access to approved treatments. Denial of VNS would further reduce their treatment options. The approval of VNS treatment should be based on scientific fact. The effectiveness of this treatment is well established and meets sufficient criteria to warrant FDA approval. VNS is an effective treatment for treatment resistant depression. Clinical work supports this. It is cost effective morally and ethically and this treatment must be approved.

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My comment is purely as a clinical psychiatrist treatng many patients with treatment resistant depression.I was extremely disappointed with the decision not to provide coverage. It is hard not to view it as part of the prejudice against mental illness and provision of services to those with serious mental illness. Certainly the decision was wrapped in "scientific" justification but since coverage is provided for many surgical proceedures for which adequate controlled trials do not exist (back surgery is a good example)it is hard to see it otherwise.

Depression is the number 1 disabling condition-Murray & Lopez "The Global Burden of Disease"Treatment resistant depression is real and probably genetically and neurophysiologically different.

I do not understand how the research required by your panel could be ethically be undertaken on this patient population.

I was initially sceptical about VNS but I have seen a woman depressed and on Social Security Disability for years recover sufficiently to return to work.

I have another patient, denied coverage, be disabled by ECT and its cognitive consequences. He hovers between life and death since he is constantly suicidal.

These may only clinical anecdotes but they constitute the real patients we see that would never be allowed in trials accepted by the FDA or obviously your elite panel.

I strongly for my patients sake ask you to reconsider your decision.

David J Wood MD FRCPC

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On behalf of the Kansas Psychiatric Society (KPS), the medical specialty society representing Kansas psychiatrists, I am writing in response to the CMS request for public comments on the re-consideration for national coverage of the Vagus Nerve Stimulation (VNS) system for the treatment of Medicare beneficiaries with treatment resistant depression (TRD).

Given the existence of a significant population of Medicare patients with TRD, who have a clinical history that clearly shows that there are no other medically beneficial treatment alternatives available to them, and given the FDA’s approval in July 2005 of the safety and effectiveness of VNS for the treatment of major depressive disorder, it is our medical opinion that VNS is, as defined by §1862(a)(1)(A) of the Social Security Act, “reasonable and necessary” for the treatment of those Medicare patients with treatment resistant depression. The criteria for coverage should be consistent with those delineated in the request; including that coverage be limited to those patients who have tried and failed at least four antidepressant treatments of adequate dosage and time; and who have either previously been treated with or refused treatment with ECT, or previously been hospitalized for depression. At the very least, Clinical Evidence Development, the program by which CMS funds technology like this, should be authorized, that could include a national registry of patients utilizing VNS, to permit on-going clinical research.

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March 6, 2007

CMS
Attn: Beverly A Lofton, MHA
RE: NCA for VNS for TRD (CAG-00313R)
C1-09-06
7500 Security Blvd
Baltimore MD 21244

Dear CMS:

I have been treating depressed patients since 1981. Many of them respond reasonably well to antidepressant medications. However, there are several patients who continue to be depressed despite their present antidepressant medications.

For the past year, I have had the opportunity to have two of my TRD patients implanted with the vagus nerve stimulator (VNS) and they are doing better, staying out of the hospital, thus saving money in the long run.

I have several other patients who are waiting for the same opportunity. Are we going to deny them this “pursuit of happiness” because of this misperceived savings? How can we spend billons of dollars in Iraq and Afghanistan and deny hope to our own people with TRD? How can we continue to “spend” troops overseas while we are trying to “conserve” the precious lives of our patients here. Our priorities are misdirected, to say the least.

Lastly, if you had a relative or friend with TRD—would you deny him the chance to recover and be a productive and contributing citizen. If CMS does not do anything about this impasse, who else will? I’d like to think that CMS stands for “Can Manage Successfully.”

Thank you for a prompt and favorable reply.

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My name is Monica E. Oss, and I am the Chief Executive Officer of OPEN MINDS, a national management consulting firm focused on behavioral health benefits, financing, and system design. I am also the chair of the newly-founded National Task Force on Consumer Access to Emerging Neurotechnologies. I would encourage CMS to facilitate access to VNS therapy for consumers with treatment-resistant depression (TRD). For many consumers with depression, traditional pharmacological interventions provide relief from symptoms and restore life functioning. Unfortunately, there is a group of consumers (approximately 30%) with TRD for whom pharmacological interventions and/or ECT are not effective. For these people, VNS represents the only available treatment option.

In addition to the issues of compassion and consumerism that should warrant access to VNS therapy for individuals with TRD, I would like to point out the economic issues as well. Individuals with TRD, as a group, are high-cost users of the health care system. In addition, TRD renders many individuals unable to function fully in life and in work. For these individuals, when VNS is effective, it also represents significant economic cost savings for both health plans and for society.

The following is a white paper, “Issues in Access to New Treatment Options for Individuals with Severe Depression” to include with my testimony. This white paper summarizes the discussions of the recent meeting of the National Task Force on Consumer Access to Emerging Neurotechonologies and has a direct bearing on the current deliberations about coverage for VNS therapy. While there is work to be done in establishing new standards for evidence of efficacy of treatment for chronic conditions such as depression, facilitating timely access to VNS for consumers with life-threatening depression is essential.
_______________________________________________
White Paper:
There are a wide range of new technologies that will soon be available to consumers to address mental health, neurological, and intellectual disability problems. However, it is likely that these new treatments will not have the maximum clinical or financial impact possible due to both a lack of standardized payer policies to assess the appropriateness of the technologies, and challenges facing service provider organizations in adapting these new technologies to their clinical and administrative management structures. To proactively address these pending challenges, the National Task Force on Consumer Access to Emerging Neurotechnologies was formed.The Task Force was founded with the purpose of reviewing and responding to issues of policy, financing, and practice that are shaping consumer access to emerging neurotechnologies. The Task Force is comprised of health plan executives, academic researchers, clinical professionals, policymakers, and program administrators devoted to exploring the future of neurotechnologies. These stakeholders are interested in assuring, and capable of affecting, appropriate and equitable access to emerging neurotechnologies for consumers with mental health, behavioral health, and neurological conditions. The focus of the National Task Force is three-fold:

Although NAMI Rhode Island does not favor one form of treatment or therapy over another, we have seen evidence with our own eyes and in our own office that VNS can and does work. We should be counting the lives saved, not the dollars spent. As you are no doubt aware treatment resistant depression is very difficult ,to treat and the only hope until now has been medications which have their own setbacks and side effects. We are debating coverage and payment when we should be encouraging exploring non-medication means of treatment.

I have watched helplessly as those with Mental Illness suffer repeated hospitalizations or suicide attempts. The toll it takes on the person with depression and their family is monumental.

After thirty years of severe suffering, one of our office staff had the VNS implanted. The change it has brought about for both her and her entire family has been unbelievable. She is now learning how to experience life again, and is considering full time work when just a few years ago she could not get out of bed.

The cost of repeated hospitalizations is much higher than the VNS treatment option, We will save both money and lives using VNS.

We would ask that you allow psychiatrists who have worked with TRD patients to be the ones who make the decision as to whether or not VNS should be used. Insurance Companies should not dictate treatment options. Non coverage for Medicare patients is opening the door for increased risks of sucide. We must Preserve access to life saving medicines. Patients and doctors should determine which medication is the right choice, not arbitrary limits on coverage.

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Dear CMS,

Depression is a serious illness and a major public health problem. Sound epidemiological studies show that at any time around 17 million Americans have clinical depression meriting treatment. Fortunately, for some, antidepressants and psychotherapies offer the chance of relief and of regaining function and quality of life. Unfortunately, for others, these standard treatments will not work for a variety of reasons. Estimates are that about 20% of depressed patients will develop Treatment- resistant Depression (TRD). Increasingly, TRD is a well-recognized problem and a clearly defined entity. My clinical practice at UCLA, a major tertiary care center, is comprised of many of these patients. Indeed, about 75% of my practice consists of referrals from primary care and mental health specialists of patients for whom standard antidepressant regimens failed. A significant portion of these patients are referred for electroconvulsive therapy (ECT), which, up until recently, was the only proven effective alternative for TRD. However, as Medical Director of the ECT Program at UCLA, nearly 35% of patients referred are not appropriate for ECT or will not accept ECT due to concerns about side effects. Of those TRD patients treated with ECT, the response rate is between 50-60%. Additionally, the relapse rate after ECT remains very high. Clearly, other alternatives are needed for this very ill patient group. For all of these patients, another alternative treatment consideration already exists, to wit, Vagus Nerve Stimulation therapy (VNS). My clinical experience with VNS therapy this past year may help elucidate why I think CMS must provide coverage for this treatment in an appropriately selected patient.

Since August 2006 I was referred 10 cases for VNS consultation. A comprehensive VNS consultation is required prior to implantation and is based upon a rigorous clinical assessment and documentation of past depression treatment and failure, ability to follow-up according to necessary protocol, and criteria set forth for VNS implantation by the Resnick Neuropsychiatric Hospital at UCLA. This policy strictly adheres to FDA labeled indications and incorporates in an iterative process the extant literature regarding management of TRD and application of VNS therapy. Of the cases referred to me, 8 were female and 2 were male. The average age was 53 years. The most common diagnosis was Recurrent Major Depression, severe without psychosis. The average duration of the current episode was about 29 months and nearly 95% were not able to work. None of the patients were actively suicidal. All had tried and failed more than 4 antidepressant medication trials in the current episode, and had undergone more trials in their lifetime. Most had undergone various combination strategies that were fraught with medication side-effects, which in my opinion, is an indication of the seriousness of their illness and the measures to which patients will go to find relief. All had been in psychotherapy or tried other psychosocial programs. Their average clinical global impression of illness (CGI) score was 6.3, placing them among the most severely and chronically ill group. Of these 10 patients, 9 had previously been referred for ECT and 4 had actually received ECT in the past without benefit and some had experienced severe cognitive side- effects.

Ultimately, 8 patients were considered appropriate for VNS therapy but only 1 was able to be implanted so far. Another patient decided against VNS therapy on her own primarily due to concerns about its cost. Interestingly, she was on Medicare disability due to chronic mental illness. She remains gravely ill. The remaining 6 patients now await a decision from their carriers regarding coverage. In discussion, all carriers point to CMS as a guiding opinion leader in consideration of offering VNS coverage to their patients.

The outcome of the 1 patient who was able to be implanted merits some discussion. He and his family agreed that his clinical information could be shared. Seen last August 2006, he was the first VNS consultation and my first patient to be implanted. His illness began in adolescence and was marked by repeated hospitalizations until his late twenties. His primary psychiatric diagnosis is Major Depression, although other psychiatric comorbidity exists. He was not functional and essentially home-bound. During one of his past hospitalizations, he was referred to ECT and successfully treated, but his response did not hold and he relapsed. Repeated courses of ECT were able to help, but he began to develop persistent cognitive and memory side-effects. As his treatment response to subsequent ECT courses was less optimal, aggressive medication manipulation continued and he ultimately stabilized on clozapine along with other potent psychotropics. The best that could be said was that he was alive and out of the hospital.

Then VNS was started. After about 6 weeks, the change was truly remarkable and an awakening of a new person. Previously withdrawn, aloof and fearful, he began to venture out with his family and began to make friends. Previously unable to be unattended, he began to request more independence. His mother, who is his primary caretaker, reported that “it was a miracle. I never knew he could be this way. It’s a normal person that I see now.” By about 3 months he reached maximal improvement. Unfortunately, around the first of this year he sustained a setback, but even here his downturn was only temporary and not a complete relapse. In fact, his relapse was brief and did not encompass suicidality or psychosis, which is completely unlike any of his past relapses. He was able to avoid hospitalization and another course of ECT, and importantly, he was able to be safely managed as an outpatient. Both the patient and his family remain very satisfied with VNS therapy and cannot believe that these past 6 months have gone the best ever.

With the above case described, I hope that CMS understands why I remain committed to offering VNS therapy to the appropriate patient. VNS is not for everyone and the response to VNS therapy cannot yet be reliably predicted. However, TRD patients require another alternative. The cost of disability is only outweighed by the years of suffering and lost quality of life that patients and their families must endure. Thus, the recent proposal by CMS not to provide coverage for VNS therapy was very disappointing. Although some of the criticisms of the data are fair, and better, more definitive studies are needed, VNS therapy stands ready to be offered clinically to the appropriate patient once rigorously evaluated by a trained clinician. Programs should develop VNS policies that enunciate the criteria on which patients would be implanted.

But, as stated in my last posting, leadership is needed, and it must come from CMS, which is recognized across the industry and the medical profession as the major player in setting coverage policy broadly. It is a terrible responsibility, but one that must be duly exercised. Concerns about the cost of a device must be weighed by the cost of disability and of lost productivity. Concerns about the reliability of the study data must be understood in the context of recent data from STAR-D, which showed that after a second medication trial, subsequent pharmacological antidepressant challenges were not likely to be either efficacious or effective. Indeed, in this light, the VNS study data appear to be quite real. Concerns about overuse and abuse are not supported by my recent clinical experience. What is evident is that VNS therapy is a much needed treatment alternative for a very chronically and seriously ill patient group. Our patients still need the hope of a better future.

Sincerely,
Randall Espinoza, MD, MPH
Associate Clinical Professor and Vice Chief of
Staff Department of Psychiatry and Biobehavioral
Sciences Geffen School of Medicine at UCLA
Medical Director, ECT Program UCLA
Neuropsychiatric Institute and Hospital

300 UCLA Medical Plaza, Suite 2420
Los Angeles, CA 90095

(office) 310-206-1544
(fax) 310-206-8058

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I have had several patients that have suffered with severe depression for years and I have not been able to get VNS therapy for them because of lack of authorization from insurance companies. This has been very frustrating for myself and my patients. I believe that the literature supports that this treatment can be helpful for at lease 20-30% of treatment resistant patients and for these patients it can really be a lifesaving treatment. Clearly because of the cost involved this procedure shouldn't be used without any oversight but to not be able to offer it to patients when everything else has failed is very difficult. I also believe that if this was a cancer treatment or a treatment for AIDS that it would have been much more readily accepted and that there is a mental health bias involved here.

Sincerely,

Joseph T. Bergs,MD
Board Certified, Adult and Child Psychiatry

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March 5, 2007

Jyme H. Schafer, MD, MPH
Coverage and Analysis Group
Office of Clinical Standards and Quality
The Centers for Medicare and Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244-1850

RE: Reconsideration request for National Coverage Determination 160.18 (CAG-00313R)

Dear Dr. Schafer,

The American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS), representing organized neurosurgery in the United States, appreciate the opportunity to comment on the above referenced draft coverage decision memo regarding Medicare coverage for Vagus Nerve Stimulation (VNS) for treatment resistant depression (TRD).

Patients with treatment resistant depression have very limited options. For patients who have failed medical treatment and who have either been treated with, or refused treatment for, electroconvulsive therapy (ECT), VNS has been a safe and useful procedure. Published studies on the effectiveness of VNS for this group demonstrate an efficacy greater or equal to the effect of additional medication. The acute phase trial ¹, which looked at efficacy at 10 weeks, failed to show a statistically significant response; however, follow up studies ^2,3 demonstrated increasing efficacy over time. This was compared to an observational control group and found to be statistically significant at 1 year 2. Thus it appears that longer time points are required to assess efficacy of the device. Similar findings of increasing efficacy of VNS therapy over time have been observed in the epilepsy population ^4-7.

The AANS, the CNS, and the AANS/CNS Joint Section on Stereotactic and Functional Neurosurgery concur with comments submitted by the American Psychiatric Association (APA) on September 6, 2006, which support Medicare coverage of VNS for TRD in patients who are deemed appropriate candidates for this device. As neurosurgeons, we look forward to the ongoing collaboration with our colleagues in psychiatry in bringing this method of treatment to these patients.

The FDA felt that this device met the legal standard of reasonable assurance of safety and effectiveness and recommended further studies. We also would like to see more studies of this promising procedure to add to our understanding of the benefits and limits of this device and its place in the treatment of this life threatening disorder. We feel that, at a minimum, VNS for TRD should be covered in clinical trials.

Thank you for considering our recommendations. Please contact us if you have any questions or need additional information.

Sincerely,

Donald O. Quest, MD, President
Douglas Kondziolka, MD, President
American Association of Neurological Surgeons
Congress of Neurological Surgeons Attachments: September 6, 2006 Comments of
Pedro Ruiz, MD, APA President Staff Contact:
Catherine Jeakle Hill, Senior Manager,
Regulatory Affairs
AANS/CNS Washington Office
725 15th Street, NW, Suite 500
Washington, DC 20005
Office: 202-628-2072
Fax: 202-628-5264
Email: chill@neurosurgery.org

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March 6, 2007

TO CMS:

I am writing to comment on the proposal by CMS that states: “CMS is proposing that there is sufficient evidence to conclude that vagus nerve stimulation is not reasonable and necessary for treatment of resistant depression. Accordingly, we propose to issue a national noncoverage determination for this indication.” > For approximately 30 years I have been a practicing psychiatrist. I have worked in private practice, in full time academia, and in the public sector. I am not on any Speakers Bureaus from Cyberonics or other VNS company and have received no financial incentives with the exception of attending a lunch meeting when VNS first gained FDA approval for treatment resistant depression. I do not insert the VNS device, nor do I do the dosing adjustments. I have referred patients for VNS.

I believe a decision by CMS to issue a national noncoverage determination for VNS for patients with treatment resistant depression is detrimental to the health of patients relying on CMS for their health care and promotes a two- tiered system of care.

It seems that a major reason for this is “The concept of treatment resistant depression is vaguely defined, subject to varying determination, and until a scientifically valid definition exists is of little help in treatment selection for individual patients…” I believe that any reasonable psychiatrist knows that there are patients with “Treatment Resistant Depression (TRD).” The concept is real. The criteria defining who actually is in that group may need refining. For this reason, care should be exercised that CMS does not throw out the baby with the bathwater! In granting approval to Cyberonics for VNS treatment for depression, FDA listed criteria which could approximate a definition of TRD. I use the FDA criteria as a “Starting point.” I only refer patients for VNS if, in addition to FDA criteria, the following are also true:

(1) The patient failed to respond to a course of Bilateral electroconvulsive therapy (ECT).

Or - (2) They responded to Bilateral ECT, but did not sustain the response with maintenance ECT.

Or - (3) There is an significant medical contraindication to ECT that is not also a contraindication for VNS.

And – (4) In addition to new antidepressants, they have also been unsuccessfully treated with an older tricyclic antidepressant and with lithium.

I am not saying that the criteria I use should be used by CMS. I am saying that CMS would be doing the American public a service by coming up with criteria that they find acceptable that would still allow these seriously ill and suffering people to receive a treatment that may help them – especially when there is no other treatment option that CMS can offer instead. Completely eliminating coverage for VNS allows these patient with TRD no hope of recovery. Thank you for your consideration.

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As a hospital psychiatrist I see many patients with treatment resistant major depression. Certainly, CMS is aware of just how poor a patients chances are for complete recovery once there has been multiple failed meds. ECT is an option that many patients are afraid of for some legit reasons. Even those patients that try ECT may not respond. If there is an ECT response there are often intolerable side effects, and transient benifits.

The FDA reviewed the 1 year data and approved VNS for the TRD patients. There is now 2 year data. Unless you consider the context of TRD the data is not overwhelming. There are weaknesses in the data on VNS. However, there are flaws in all research, and in psychiatry in particular there are many obstacles in research. The VNS data for TRD is at least as solid as for Epilepsy, so it is hard not to view the CMS stance as another example of discrimination against people w/ mental illness.

In what limited exposure I have had (4 cases) I have seen improvemnt that was striking in one case , and subjectievlty reported as positive in the other 3. This beforehand very hopeless feeling group of patients has started thir own chapter of the Depression and Bipolar Support Assoc.(DBSA), and other patients are waiting. I am also a taxpayer , and I understand that VNS is very expensive compared to other outpatient psychiatric treatments. For the good of these most difficult to help patients CMS should reconsider the absolute no support stance for VNS. Please set a high bar for qualification (ECT failure, 10 meds , everything in STAR-D tried) ,and evaluate from there including long term patterns of less hospitalization. I am trained to adjust VNS device , but do not have any direct financial relationship tpo cyberonics.

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I am an adult psychiatrist with a practice in Texas and I am inquiring specifically about CMS’ proposed non-coverage policy for Vagus Nerve Therapy (VNS) for Treatment Resistant Depression. Many of the items in your proposed ruling are contradictory to findings that led the FDA to approval. Almost all of the VNS patients under my care (8 of 9 so far) have not only met or exceeded the requirements of the indication, but are showing better outcomes than what was shown in the original studies. This is also reflected in the “TRD Outcomes” database as required by the FDA of Cyberonics. It also concerns me that CMS minimizes the findings by the FDA that VNS was found to be safe an effective. The draft decision ignores the experience of over 45,000 patients that have received VNS therapy for epilepsy since 1997.

Patients for which VNS is indicated have suffered for dozens of years. These patients cannot get out of bed, clean their own home, cook or work. Many have tried and failed different types of anti-depressants medication, Electroconvulsive therapy (ECT), psychotherapy. This group of patients has been considered hopeless by insurance, family members and frequently even their own psychiatrists. As an adult psychiatrist with extensive VNS experience, patients are seeking my help as a last chance effort before they commit what they perceive as their final attempt of suicide. Fortunately, I have prescribed VNS and coverage was granted for 9 patients. These patients are now opening themselves to a new side of life that, before, was a distant memory. They are getting out of bed, working and becoming mentally well again. They are not incurring several thousands of dollars in insurance claims due to hospitalizations or ECT sessions. They are not filing disability claims because they are now able to work and support themselves independently. If a person has a heart, kidney, stomach, or Alzheimer’s condition each patient is treated either by a written coverage policy or on a case by case bases. VNS is completely covered for seizure disorder!! How can patients with chronic depression be denied the same therapy where other patients are not denied access??

Please reconsider the proposed non-coverage decision and give me the tools necessary to treat my patients appropriately. I can be reached at (361) 937-7182 should you havequestions.

Daniela Badea- Mic MD

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1. Even the most conservative estimates of TRD prevance (1/2 0f 31% from STAR*D) is 15% of cases of depression.
2. This translated to over 1 million persons currently.
3. Depression is 1st leading cause of YLL in terms of disability and 4th leading cause of disability in DALYs.
4. The only FDA-approved treatment for TRD is VNS.
5. FDA found VNS to be safe and effective.
6. CMS may disagree with that decision, and may question the evidence on which the FDA relied. However, CMS should cover the procedure until a joint comittee of FDA representatives and CMS representatives can agree on a conclusion.
7. Clinically, it has been effective in about 1/3 of the 15 patients in my practice who have received it.
8. CMS needs to do the following: for all available treatments CMS needs to determine the cost-effectiveness in dollars per QALY saved.
9. Then, like most other countries which spend less per capita on healthcare but have better incomes, a maximum dollars per QALY saved limit should be imposed an approval for treatments.
10. Cost-effectiveness should be the over-riding issue, but it should be determined by epidemiologic analysis. The methods have long been available.
11. If not already reqiured, FDA should mandate a long- term phase IV trial with large N.
12. DISCLOSURES: I, nor any family members, own stock in Cyberonics. I am a physian participaing in the TRD registry with minimal financial re-imbursement. I am not a consultant or speaker for Cyberonics.

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As a University of Missouri, Columbia psychiatrist whose practice has a very high proportion of treatment resistant mood disorders I am particularly disappointed in the decision of CMS not to cover Vagal Nerve Stimulation in the treatment of Treatment Resistant Depression. I have been in clinical practice for almost 20 years and using Electroconvulsive Treatment (ECT) for as long. While it is a viable option for some of the most severe cases there are still those who need more. I am one of the few doctors in this part of Missouri who provides not only medication management but also (ECT) and Vagal Nerve Stimulation (VNS) for treatment refractory mood disorders, generally Major Depression. I have been using VNS for about 18 months with excellent results. On average my patients are both on public assistance and private insurance, have 5 to 10 years of unremitting depression and have failed at least 10 antidepressant trials which would be of suitable dose and duration to be therapeutic. I have used both the Hamilton Depression Rating Scale and the Montgomery Asburg Depression Rating Scale and find little disagreement in the overall scores, even when following both scores on the same patients. Further it is not simply my opinion that these patients are improving but it is their scores on the rating scales and the patients own opinions. About half of my patients have had a remission of the depression symptoms for the first time in many years and are now starting to get on with their lives.

These patients are often going to be found on the roles of Medicare and Medicaid and these patients have had many, many medication trials generally with poor responses. While there may be some controversy as to how Treatment Resistant Depression is defined, there is little disagreement that it does exist. It must be remembered that Vagal Nerve Stimulation (VNS) is a treatment option for Treatment Resistant Depression. Not everybody will be a candidate for it and many will likely decline, just as some will decline ECT. What will be unfortunate will be if those who would be good candidates and want to try this treatment have it removed as a possible treatment without even being given the chance to get better. Please reconsider the arguments for the Vagal Nerve Stimulation as a method of treating treatment resistant Depression. While there are many interesting academic points and controversies it needs to be remembered that these are people who have little hope with treatment as usual and might be benefited with this treatment alternative.

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To Whom it May Concern at CMS,

I am presently a treating psychiatrist to severely mentally ill patients who have been followed for Schizophrenia, Schizoaffective disorder, Bipolar disorder and Major Depression, Recurrent (primarily treatment resistant depression). Over the last 17 years, I have experience with mental illness from TCAs, MAOIs, SNRIs and VNS. Presently the population I treat is one that is defined by treatment resistance with extensive costs associated with their care. To keep these individuals out of the hospital and in the community is a great feat, yet to have them improve in their longitudinal care is an even greater feat. Presently 7.6% of my patients would be classified at treatment resistant depression in terms of continued expression of depressive symptoms in the face of heroic pharmacotherapy interventions. The primary step of patients getting referred to me is through treatment failure within the existing mental health system with repetitive hospitalizations and instability in the community. In the Arkansas mental health system, referral to the GAIN program is for a defined treatment resistant population who meet criteria for Assertive Community Treatment. In another area of treatment, my private clinic, the patients are again referred after failure with traditional private treatment that includes ECT, psychotherapy and pharmacology. Within that context, I would like to share the data I have continued to collect on my patients who have received VNS therapy while under my care.

I have significant concerns about how CMS issued a proposal for coverage of VNS to a negative result. Given that none of the individuals listed on the determination are psychiatrists, the discussion that follows focuses on the conclusions made about VNS and the decision rendered on VNS:

Please reconsider your decision to not cover VNS Therapy. My patients and their doctors deserve the option to have this FDA approved therapy to treat treatment resistant depression. I educate patients about VNS Therapy. They share with me their daily struggles with depression, they can't work, but want to. They can't take care of their families, but they want to. They try medications that cause wt gain, liver problems, fatigue, and still they continue to search for something to relieve their symptoms. They try ECT, they are in and out of the hospital, and are so ashamed that they can't get control of their lives. But still they struggle on everyday. I know VNS Therapy is not a magic cure, but there is a select group of patients that have nothing left to try. Please give them a chance to live.

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I am writing requesting the approval of coverage for VNS Therapy for treatment resistant depression. I am a psychiatrist and a mood disorders researcher. My main interests are brain stimulation modalities like vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS) and functional neuroimaging. I have received primarily federal and private foundation funding. I have also received in the past research funds and consulting fees from Cyberonics Inc. Less than 10% of my salary is supported by industry. In what follows, I highlight the need for longterm treatment for treatment resistant depression patients and point out emerging mechanisms of action that could begin explaining VNS clinical impact.

I, as a clinician in South Carolina and an expert on mood disorders research share with you the goal of getting our patients the care they need, to sustain their responses to treatment and by doing so improve their quality of life and the lives of people around them. In my comment, I try to bring out the serious problems many of our seriously depressed patients are facing, some of the limited choices they have and how, medicare and us clinician, we could work together and advocate on their behalf and thus bring them the treatment they need.

Depression is a significant public health problem. It affects approximately 20% of the population and can present at all ages and life stages. Luckily, treatment resistant depression accounts for only a small but still significant portion. The social and economic burden on the individual, society and the health system is estimated to be higher than 150 billion dollars. Because of the potential chronic and relapsing nature of the illness, the World Health Organization (WHO) ranked depression in 2000 as the 4th leading contributor to the global burden of disease among medical conditions. Treatment resistant depression represents a heterogeneous sub-group of patients that share a history of failure to more than 1 adequate trial of antidepressant therapy in the current depressive episode.

Even in randomized controlled trials of nonresistant, uncomplicated major depressive disorder (MDD), only 50-60% respond to any one medication, and of this group, only 2/3 (or 35% of the initial group) become symptom-free. This is important as it will put the results obtained with VNS Therapy in perspective and highlight the value of the therapy. The recently published results of a recent large, multi-center, study of depression funded by the National Institute of Mental Health demonstrated the limitations of psychopharmacological approach to this disorder. This STAR-D trial showed that after three independent and different pharmacological treatment strategies at very best only 70% of patients remit. More so, this trial illustrated a pattern of diminishing clinical returns in which each successive pharmacological treatment failure predicted a worse prognosis using any given future pharmacological treatment. Clinicians often have to switch their patients to other treatments, or combine medications. Even if some symptom benefit can be obtained with 3-4 medications simultaneously, the medical risks and side-effect burden can become excessive. Psychotherapy (provided in many different forms) is only helpful to a sub-group of patients. Other interventions, like ECT, are generally applied in treatment resistant cases and if effective still require long-term treatments. In many cases(>50% in previous medication nonresponders), the medications do not sustain a remission. Some patients exhaust nearly all therapeutic options and revert to psychiatric neurosurgery as a last resort.

In light of this serious health care problem and after considering the available data put forth by Cyberonics, the U.S. Food and Drug Administration (FDA) approved in 2005 VNS Therapy System for the 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. VNS Therapy is also indicated for the treatment of patients with refractory partial onset seizures. It has been so since the mid 1990's which gives us, along to the clinical data in depression, a good safety profile drawn from a much larger pool of implanted patients.

The antidepressant effects with VNS Therapy were initially found in an open acute study and longterm follow up. Despite negative findings in a double-blind acute study which is the source of the controversy around the FDA approval, the naturalistic 2-year follow up study of ongoing adjunctive VNS therapy in 2 independent cohorts (D01 and D02) severely depressed patients found the antidepressant response to VNS therapy increased over time and initial improvements were largely sustained for the group at 2-year. In general, 2 out 3 of initial responders were likely to show continued clinical benefit after 12 months of VNS therapy and 1 out 2 after 24 months. The longterm results show delayed and consistent improvement with substantially fewer relapse rates than in other studies with similar level of treatment resistance subjects which could range up to 70%. The mechanisms of action underlying these intriguing response patterns to adjunctive VNS Therapy remain larger unexplained. My group has been actively involved in conducting mechanisms of action studies (in part funded by Cyberonics) using functional imaging. We have shown that changes in the ventro-medial prefrontal cortex activity may account for the delayed antidepressant response to VNS Therapy. It is then maybe plausible to conceive that with intermittent chronic peripheral vagal stimulation ultimately lead to a change in the functional activity of a mood regulating network and thus ultimately lead to a clinical improvement. I have attached a copy of this work published in a top tier journal.

I should mention that in addition to research in brain stimulation, I direct a Mood Disorders Clinic (MDC) whose mission is to disseminate and advance state-of-the-art science and treatment for clinical depression. The 2 main therapeutic modalities currently in place are Electroconvulsive Therapy (ECT) and VNS Therapy. The clinic provides comprehensive evaluations and treatments of individuals with treatment resistant depression. Consultations are available for both inpatients (ECT) and outpatients (ECT and VNS Therapy). Upon referral from a health care provider, individuals receive a thorough psychiatric and medical evaluation, to determine if they are appropriate for any of these 2 treatment regimens. The collaboration between patient, family, referring physician and the Clinic's health care providers is key. With VNS Therapy, since it is a long-term treatment, the Clinic monitors the device over time and provides feedback to the primary physician. When needed, it can also provide additional input for optimal clinical management. The clinic has guidelines for when to recommend VNS Therapy. These include:

• Patient must be between 18 and 65 years of age.
• Patient must have major depressive disorder (MDD) or bipolar disorder (BD), depressed phase.
• Patient must have a clear need for long term treatment as evidenced by:
  
  1. long standing depressive illness (ill for _ 5 years since first onset of the MDD or BD), and
     
  2. the presence of at least 3 major depressive episodes (MDE) including the current MDE, or a current MDE lasting _ 2 years.

There must be written documentation of at least 4 failed adequate antidepressant treatments. An adequate antidepressant treatment is an established treatment that has been delivered at an adequate (i.e., therapeutic) intensity and duration. Treatments for which there is good published evidence of efficacy (i.e., established treatments) include any FDA approved antidepressant, electroconvulsive therapy, thyroid augmentation, lithium augmentation, buproprion augmentation, any atypical antipsychotic augmentation and any stimulant augmentation. For bipolar disorder, established treatments also include clozapine and lamotrigine. A failed treatment is defined as a failure to reach remission in the acute phase of treatment or a failure to achieve sustained remission in the continuation or maintenance phase of treatment. In our clinic we perform the antidepressant history form (ATHF) for each evaluation. The ATHF rates the adequacy of antidepressant treatment based on diagnosis (unipolar or bipolar depression, with or without psychotic features). The ATHF was originally developed to classify research subjects presenting with major depression as treatment refractory, and uses stringent dose ranges to define treatment adequacy. For the treatment to be considered adequate, it must be taken for at least 4 weeks except in the case of ECT. The ATHF only rates as adequate treatments those approved by the US FDA for major depression or for which there is substantial evidence of antidepressant efficacy in the literature. Note that psychotherapy and hypnotics are not included in this classification. Patient does not have fixed delusions or a diagnosis of psychotic depression, schizophrenia, or schizoaffective disorder. Patient is not at imminent risk of suicide (as judged by the prescribing physician) and has not attempted suicide in the immediately preceding six months. The prescribing physician must be a psychiatrist who has experience treating patients for TRD.

Note: I should mention that although previous ECT is clearly considered in the assessment of treatment history, we don't consider that it is a necessary gateway for proposing VNS Therapy. We now have ample evidence that ECT and VNS Therapy appear to have different clinical effect with mainly a different time course, and failure to ECT has not directly predicted response to VNS Therapy.

Of course, there are contraindications for VNS Therapy as it cannot be used in patients after a bilateral or left cervical vagotomy. Do not use short wave diathermy, microwave diathermy or therapeutic ultrasound diathermy on patients implanted with a VNS Therapy System. We also consider other medical conditions that may present relative countraindications. I have reviewed in more details VNS Therapy and what are the research steps needed to move forward in our understanding of the therapy in a recent article published in the December 2006 issue of Current Psychiatry Reports. While additonal acute double blind placebo controlled studies are needed to demonstrate acute efficacy, the longterm available data support VNS as a viable option in the standard of care of treatment resistant depression.

In summary, I believe that treatment resistant depression has a tremendous burden to the patient, his/her family and our communities at large. At one year, adjunctive VNS Therapy will double the chances of improving by over than 50% from baseline and will substantially help 1 out of 3 patients. One other third will get some benefit. Most importantly, 2/3 of the patients who acutely respond to VNS will hold their response at 1 and 2 years. This presents a change from most of all other FDA approved treatments for chronic remitting depression. With these results and above suggested guidelines, I ask Medicare to pay for VNS Therapy for treatment resistant depression.

I look forward to your final policy to this regard so we can work together to meet our missions and provide our patients the care they need.

Sincerely,
Ziad Nahas, MD, MSCR
Associate Professor
Director, Mood Disorders Program
Medical Director, Brain Stimulation Laboratory
Medical University of South Carolina
Institute of Psychiatry
67 President Street, room 502 North
Charleston, SC 29403 USA

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Dear Sir or Madam:

I am an academic Psychiatrist who treats mood disorders including TRD, and I participate in research involving VNS (San Antonio site principal investigator for the Cybernoics D21 trial). These experiences give me unique appreciation of TRD, its consequences and treatments. TRD is an illness where standard therapies do not work. The result is that patients and their families suffer tremendously. From a public health point-of-view, TRD causes our society financial strain in both direct care and indirect losses of productivity and burden on the family. Without any effective treatment VNS offered some hope. However, I was disheartened by the analysis and conclusions of CMS regarding VNS.

It is unclear how the reviewing agencies, TEC, CTAF and CMS came to the conclusions that they did. With regards to the TEC evaluation, the following conclusion is simply wrong: “… given the well-designed negative RCT and the fact that this is a single group of patients in an observational trial, it is early to conclude that the new technology of VNS improves the net health outcomes as much as or more than the established alternative of TAU with medications and/or electroconvulsive therapy”. The RCT was not negative. Rather, this meant that the primary outcome measure of the RCT was not significant. There was a valid measure of depression in the secondary measures that was significant. Also, they say there is no evidence that more established therapies will not work as well as VNS. Unfortunately, they miss the point. There are no therapies for TRD; it is treatment-resistant. With my patients I have tried nearly every antidepressant without benefit. Some would indeed benefit from ECT, but due to their misunderstanding of the procedure these patients will not elect to have it.

The CMS conclusion is also flawed: “The concept of treatment resistant depression is vaguely defined, subject to varying determination, and until a scientifically valid definition exists is of little help in treatment selection for individual patients. In the evaluation of antidepressant treatments, randomized, controlled trial design is particularly important due to the natural course of the disease, where symptoms wax and wane and there may be spontaneous remission, and the placebo effect. The pivotal randomized controlled trial of VNS, subsequent to a pilot study, failed”. The concept of TRD is very well-defined, and regardless if one defines it as a failure of four or more antidepressants, the treatment outcome is the same. That is, patients remain depressed. So if VNS can move 15% of patients from depression to euythmia, then the treatment has had a significant positive impact on the lives of these patients. Again, the D02 did not fail. It is a mistake to say that if the primary outcome did not show significance, then all the other data collected is to be ignored.

In summary, while VNS is not a treatment to be given lightly, or to the average patient with depression, the data suggests that it has a role to play in reducing some of the suffering caused by TRD.

Sincerely yours,

Peter M. Thompson, M.D.,M.S.
Associate Professor of Psychiatry
Director, Southwest Brain Bank
UTHSCSA

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3-3-2007

Center for Medicare Services

Dear CMS:

Re: Proposed Decision Memo – Vagus Nerve Stimulation for TRD Administrative
File: CAG-00313R

We are writing to you in connection with the proposed policy decision to not furnish CMS coverage for VNS treatment for patients diagnosed with depression and who are not responding to the standard, currently available treatments (antidepressant medication, psychotherapy, and electroconvulsive therapy). Both of us, as clinicians, have treated TRD patients for over 20 years and we are open to any emerging interventions that offer reasonable hope for improvement in this gravely ill population of patients. We trust you will give due consideration to our collective opinion, as well as the data we have collected in our practice and will review for you, that speaks to VNS outcomes in the real world.

Based on the evidence from the literature, about 15% of patient diagnosed with depression are not helped to any meaningful degree with the current array of clinical treatments and new ones are desperately needed. Doubtless, this patient group contributes disproportionately to the 25,000 annual deaths from suicide in the US. In this latter sense, TRD can and should be viewed as a public health emergency, in the same way as coronary artery disease and HIV infection are perceived. Thus, the unmet need is great; the question is whether VNS has the potential to meet some of this need.

We believe that VNS does have meaningful therapeutic benefit for some TRD patients. Even though we are all aware that the short-term pivotal trial of VNS failed to document a statistically significant result, we must not lose sight of the wood for the trees by focusing only on the short-term outcomes. TRD is a long term illness, and it is the long term one and two year outcome data with VNS that is most compelling. Responder rates at one and two years range from 30% to 43% depending on which data set is examined. This level of improvement over the longer term compares favorably with any other treatment available to the clinician, including ECT. It is additionally of a magnitude that cannot be simply explained away, in our judgment, by reference to placebo effects or regression to the mean. We would also ask the following pertinent question: if CMS is not fully satisfied that these outcomes are a true treatment effect, why is does not espouse a policy of coverage for a specified cohort of TRD patients so that the effectiveness of VNS in the long term can be studied to its satisfaction?

Since the original FDA approval in 2005, we at Penn have implanted 15 refractory depressed patients with a VNS device, most of these being Medicare recipients. We have collected outcome data prospectively to assess the effectiveness of VNS in this population and have used measures that can be easily utilized by any clinician who manages TRD patients in their practice (e.g. Beck Depression Inventory, CGI-I scale, Beck Anxiety Inventory and the Beck Hopelessness Scale). We have just analyzed the outcomes at 6 months for these first, consecutive 15 cases (see submitted scientific Abstract in the Appendix). Of particular interest, is that this patient population was even more ill than that studied in the VNS efficacy trials. A full 67% had failed ECT in the current episode of depression (versus 33% in the Cyberonics pivotal trial), and 87% had received ECT during their lifetime (versus 52% in the pivotal trial). Despite this, 61% (n=8) were classified as having achieved at least minimal improvement by 6 months (CGI-I > 3), and 23% (n=3) were classified as responders.

In conducting this study of real world outcomes, we used measures that can be easily implemented in practice by the clinician. Thus, we chose the Beck Depression Inventory (BDI) as our primary measure of change. Additionally, as the BDI is self-administered, we felt it would control somewhat for physician bias (in favor of a positive outcome) by telling us if the patient really felt better, and not rely only on the clinician perspective. As indicated in the abstract, the BDI showed significant improvement at both 3 and 6 months. There was a 13 point reduction from a baseline value of 37.7 to 24.8 at 6 months, effectively shifting the patient group from a severe level of illness at baseline to a moderate level at 6 months. Safety outcomes were also good with no patient discontinuing VNS due to adverse events, and side effects generally being mild and of the type that would be expected. One year outcome data for this patient group will be available by October of this year. Please note that no support of any kind was solicited or received from the VNS device manufacturer in collecting or analyzing this data. The main implication of our effectiveness data is to imply that VNS may have the potential to help patients who have already failed ECT. These are patients who have no other available, reasonable, treatment options currently.

In closing, we hope that CMS will reconsider its decision to propose non-coverage for VNS for TRD. Given the doubts CMS has expressed concerning VNS efficacy, perhaps it could consider supporting collection of longer term data on effectiveness of VNS in clinical practice for a sizeable cohort of TRD patients, as we have attempted to do here on a smaller scale. With the current policy decision, no implants can get done, and thus no answer will be forthcoming on what the true potential of VNS is to help this desperately ill patient group. Please reconsider your proposed policy.

Sincerely,

_______________________________
Michael E. Thase M.D.
Professor of Psychiatry
John O’Reardon M.D.
Assistant Professor of Psychiatry
Director, TRD Clinic
University of Pennsylvania

Appendix
Effectiveness and safety of VNS in clinical practice: outcomes at six months

Pilar Cristancho MD, Mario A. Cristancho MD, John P. O’Reardon MD.

Background: Vagus Nerve Stimulation is a novel technology for treatment resistant depression (TRD), that uses an implanted device to modulate neural networks in the brain. It is FDA approved based on longer term outcomes from efficacy trials, but no data has been reported on its effectiveness in clinical practice. We report on effectiveness of VNS in a cohort of patients with refractory depression treated at an academic medical center.

Methods: Baseline and follow up data was collected prospectively in a consecutive case series (n=15) of VNS implants performed for TRD over 1 year at the Hospital of the University of PA. All subjects remained on existing antidepressants, which were held fixed as far as clinically possible, with VNS added adjunctively. The primary outcome was change in the Beck Depression Inventory at 6 months. Secondary outcomes were changes in the Clinical Global Impression of Improvement scale (CGI- I), Hamilton Depression Rating Scale 17-item (HDRS-17), Beck Anxiety Inventory (BAI), Beck Hopelessness Scale (BHS) and Quality of Life enjoyment and Satisfaction scales (Q- LES-Q). A paired sample t-test was conducted with SPSS software (v.14.0) for changes at 6 months on an intent to treat, last observation carried forward basis.

Results: Mean age of the sample was 48 years (SD=10.1), 60% female (n=9). Diagnosis-wise the sample was mostly unipolar (66.7% MDD, n=10; 33.3% BP n=5; n=2 BP=I, n=2 BP-II, n=1 BP-NOS). The sample vas very ill with a high degree of TRD as reflected by a lifetime history of ECT of 87% (n=13) and failure of ECT in the current episode of 67% (n=10). Change in the BDI was significant at 6 months (t (11) = 2.89 p < 0.05). Similarly physician assessment via the CGI-I score showed significant improvement (t (11) = 3.07 p < 0.01). There were improvements in other secondary outcomes but these failed to reach significance, possibly due to the small sample size. By 6 months, most patients (61%) (n=8) had achieved at least minimal improvement (CGI-I > 3), and three (23%) had responded. VNS was well tolerated safety wise and no patient discontinued VNS therapy prematurely due to adverse events. One subject with a diagnosis of BP-I had a breakthrough manic episode resulting in hospitalization, which resolved quickly with medication adjustment. Adverse events were judged generally to be mild in severity and included: anxiety (23.1%), hoarseness (79.9%), dyspnea (53.8%), nausea (46.2%) and pain (15.4%).

Conclusions: VNS was found to be effective in this sample of highly refractory TRD patients. The results suggest that VNS has the potential to be helpful in patients not previously responsive to ECT. Longer term data on the clinical effectiveness of VNS are needed. (Words=438)

From: Laboratory for Transcranial Magnetic Stimulation, University of Pennsylvania.

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As a psychiatrist treating a spectrum of psychiatric disorders, it is important to me to offer my population all the possible treatments available. Unfortunately, treatment options for some become increasingly limited due to the refractory nature of their mental illness. This can be particular true for mood disorders such as Major Depression. I strongly feel that VNS offers convincing data to help those who suffer from their functionally impairing mental illness. Despite this opportunity for recovery, the barriers in obtaining VNS therapy lay mostly in access. I would like to take this opportunity to express support of VNS for treatment or resistant depression.

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Dear Medicare Decision Makers,

I am writing to express my deep disappointment about you draft national policy proposing noncoverage of Vagus Nerve Stimulation (VNS) for patients with depression that does not remit following multiple adequate trials of available standard treatments.I understand there was an abundance of positive public input submitted during the last comment period. If public comments are considered a key part of the National Coverage Determination process, why was that expression of support for access to VNS summarily dismissed in the first round of comments?

Your rationale for noncoverage does not take into account the field's growing understanding of treatment resistant depression. There has been considerable research conducted and published since the Stimpson et al 2002 article you cite. The findings generated by STAR*D are an example of how antidepressant treatment resistance is being sytematically characterized in recent years. While the precise definition of resistance may vary somewhat from one source to another, you simply cannot deny that there is exists a population of depression sufferers for which traditional therapies continue to fail. It is not reasonable or ethical to dismiss these patients as hopeless cases for which nothing can be done, especially when VNS is FDA approved specifically for this population.

I am particulary disturbed by your comments which appear to discredit the scales used in clinical neuroscience research to identify and rate severity of depression. While it is certainly true that we cannot diagnose and stage depression through simple laboratory tests like practicioners of oncology, it is altogether inappopriate to ingnore the severity of the disorders which comprise our field, by virtue of the inexact science employed in their measurement. The depression assessment scales used in the VNS trials have been used for decades by psychiatrists and researchers in the development of therapies to address major depression. Whatever issues you may have regarding their validity and precision would apply to all depression clinical trials research and not just to the evaluation of a device therapy developed specifically for the most ill of depression patients.

Your concerns about safety are particularly unfounded. The FDA found VNS to be safe and effective for depressed patients. Moreover, it is known that over 40,000 patients with epilepsy have received VNS therapy to date. There is no reason to believe that the experience of those VNS patients with seizure disorders would be different that that of patients with depression.

I consider myself an expert in the study of this disorder and in the use of VNS. I have personal experience with the treatment in my practice and I have closely reviewed the available data supporting its safety and efficacy. Certinaly there are challenges in studying disorders whose manifestations require patients' subjective descriptions of their experiences (mood, pain, sensory function, etc). However, as scientists and healers we can not become incapacitated in advancing novel medical therapies as a result of such challenges. The disorder in question is a medical one, with serious impact on human function and mortality. Clearly VNS is different than antidepressant therapies that have come before it. Additionally, the population for whom the treatment is intended is unique in the history of antidepressant clinical trials. The design employed to evaluate VNS may have been suboptimal compared with that used to study the drugs which preceded it, but I believe the evidence supports the conclusion that VNS is a useful long-term treatment for a subpopulation of patients with major depression. I hope you will reconsider and reverse your noncoverage decision and make VNS available to your patients who desparately need it and can greatly benefit from it.

Sincerely Yours,

Linda L Carpenter, MD
Chief, Mood Disorders Program, Butler Hospital
Assoc Professor, Brown Department of Psychiatry and Human Behavior

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Dear CMS,

I was quite disturbed and surprised by your position on the use of vagal nerve stimulation for treatment refractory depression. You seem to imply that treatment resistant depression is an ill defined disorder and that treatment outcomes cannot be objectively defined.

I have been practicing psychiatry for over 25 years. I currently hold the position of Research Scientist at Florida Atlantic University in Boca Raton. Treatment resistant depression is clearly defined. Michael Thase M.D. and John Rush M.D. have published extensively, in peer-reviewed journals, describing in great detail and objectivity the staging, diagnosis, and treatment options for this disorder. Any clinician having reasonable experience with patients knows that there is a subpopulation of depressed patients who have not responded satisfactorily to usual and customary treatments. These patients are the "worst of the worst". These patients are analogous to advanced cancer or HIV patients when current treatment strategies have failed. Outcomes can most certainly be measured objectively. Validated rating scales have been used for years. Physicians who are accustomed to dealing with studies related to blood cell counts or blood pressures may find rating scales used in psychiatry to be highly subjective, but that is not the case. The psychiatric rating scales used in VNS studies as well as other contemporary psychiatric studies are highly objective and validated.

I'm very familiar with the studies related to VNS. I consider myself to be knowledgeable regarding scientific method and I am an experienced clinician. My conclusion is that vagal nerve stimulation is an appropriate and medically necessary treatment option in a select group of treatment refractory patients. There is no debate among psychiatrists regarding the existence of these patients and that valid rating scales and outcome measures can be relied on to assess treatment outcomes. Using these validated measures, one can conclude that patients receiving VNS had better outcomes than those patients who continued to receive "treatment as usual". Analysis of the data confirm that this outcome was not a result of random distribution, or placebo effect. As you know, one cannot practically, or ethically, conduct long-term sham treatments in this group of very ill patients.

Your position, if left unchanged, will have a very detrimental effect on the lives of these patients and questions the scientific basis of psychiatry. I hope you will reconsider.

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I am an epilepsy specialist and prescribe VNS therapy for the treatment of intractable epilepsy. Because there is at least a ten-fold prevalence of depression in epilepsy, any neurologist using VNS for epilepsy will necessarily have a strong clinical experience in the use of VNS in depression.

I have had an extensive experience with VNS in my neurology practice. Since 1999 I have treated approximately 80 epilepsy patients with VNS. Five patients are no longer followed here and 26 patients are MRDD (mentally retarded developmentally disabled). The remaining 49 patients were reassessed for this communication.

Prior to beginning VNS therapy approximately 19 of the 49 patients suffered from depression and/or complained of the vegetative symptoms common to depression. Following VNS treatment (employing a variety of duty cycles), I have found 10 of the 19 patients with improvement in their emotional state and/or vegetative symptoms.

Of these 10 patients, three have had no further hospitalizations for depression after having been hospitalized for treatment of depression in the past. Six of these 10 patients have been able to resume driving and are employed. One patient was able to become pregnant (twice) as medications were reduced. One teen has returned to public school.

No patient has had to discontinue VNS due to adverse effects. One patient had a lead malfunction from seizure-trauma to the neck. One patient has permanent post-operative cervical hypesthesia. Reducing the bandwidth or signal frequency treats the usual side effects ascribed to VNS. Most adverse effects improve over a few months. No patients have attempted suicide following VNS placement.

In summary, this is my experience with VNS therapy in depression. This offers a real world portrait of the meaningful change in the quality of life that many individuals with depression experience due to the direct effects of VNS therapy and the indirect effect of medication adjustments.

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In the course of providing electroconvulsive therapy (ECT) for the past eight years in a university setting, I have obviously encountered a lot of severely depressed patients. While ECT helps most of them, a subset of patients remain refractory to it and to all medications. Such patients are both miserable and also high consumers of medical and psychiatric services, both outpatient and inpatient.

While the data supporting the effectiveness of VNS is obviously imperfect, it is important to have another recourse given the shortcomings of available antidepressant treatments. In my opinion VNS should be an option for the most refractory of refractory depressions, and perhaps specific parameters (well beyond the four or more unsuccessful antidepressant trials stipulated by the FDA indication) could be set for its use. Note, I have no financial ties to Cyberonics whatsoever and have never accepted even the smallest gift from the company.

Neil Scheurich

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Dear Sirs: I am the Director of Clinical Research at Sheppard Pratt Health System, a psychiatric teaching hospital, and on the volunteer faculty at the University of Maryland School of Medicine. I am also a board certified psychiatrist and a Distinguished Fellow of the American Psychiatric Association. One of my prime research interests has been in the treatment of severe, refractory mood disorders including treatment resistant depression. I was an investigator in the Cyberonics D-02 study, taking over the University of Maryland patient cohort and am a principal investigator in both the D-21 dose finding study and the Treatment Resistant Depression Registry. Cyberonics has agreed to support a study I am planning to do looking at the response of patients to VNS who have required ECT for the management of depression. I have been responsible for the evaluation, implantation and/or care of close to 40 patients receiving VNS. I own no stock in Cyberonics but do serve on the speaker panel for them. My speaking income from Cyberonics totals less than $25,000 per year.

While half of my implanted patients are currently in a blinded study of different doses of VNS stimulation, I am clear that this treatment has been a benefit for many of my patients. I have seen the ECT requirements of my patients almost uniformly be decreased at some point into their treatment. Many patients have increased their activity levels, some being able to work full or part time when they were unable to before and many able to enjoy more in their lives or have an increase in their energy levels. It is impossible to offer accurate numbers at this time due to half of my patients being in a blinded study, my best guess is similar to the D02 results. Half to 60% of patients have some significant benefit, a third meet response criteria and 15-20% meet remission criteria. I, daresay, that if we were looking at these numbers for a cancer treatment, support for it would not be a question.

I am concerned by the recent CMS proposed decision memo on coverage for VNS. While the document is well researched and thoughtful it does “miss the boat” on several issues:

1. It is true that measurements for severity and improvements in depression leave much to be desired. As well there is some disagreement in the field as to what criteria to use to diagnose treatment resistant depression. I would further argue that treatment resistant depression is a different illness than depression requiring different sorts of evaluation and thresholds to determine benefit. Even modest improvements in symptoms can be life altering for afflicted individuals. Ultimately the evaluation of depression is subjective and following the logic of your document suggests that CMS should not pay for any treatments for depression given the methodological problems of this entire field of investigation. The overall nihilistic tone especially in the absence of specific recommendations does nothing to further the endeavor of treating our patients.
2. The lack of statistical separation in the primary outcome measure which has been used by many insuring bodies as evidence VNS does not work is a straw man. Cyberonics did indeed pick too early a point in time after beginning adequate delivery of stimulation (ultimately just eight weeks) to use as their primary outcome measure. Had the outcome measure been four to six months out, the results would have likely shown separation. It does take longer for patients to respond to VNS and the data support a progressive improvement that may continue to build over 24 months.
3. Response criteria are also a problematic issue. A 50% decrease in a rating scale score is too high a barrier. We need to think about TRD more like schizophrenia where a 20% improvement is considered a significant response.
4. While I did not design the D02 study, I am clear that figuring out what would be a fair comparator group is a challenge. In general, I feel that TRD patients are generally low placebo responders but I have had the experience of desperate patients being accepted for an investigational trial may experience a lift in mood due to having a sense of hope for the first time in years. This does tend to return to baseline over the course of days or a few weeks. This well could arguably be a confounding factor for the D02 vs D04 patients but ultimately it does sort out over a few weeks as that sense of hope will die out without a clearer clinical improvement.
5. There is no clear template for the management of TRD so the goal of D04 was to allow expert clinicians free reign to take their best shots at improving patients. Despite the uncontrolled nature of the study, the numbers are similar to the STAR*D data from level 4 patients and from my clinical experience. Despite some differences as noted in your report between the D02 and D04 populations, I feel the comparison is a worthwhile one.
6. The heterogeneity of TRD patients is a continuing issue. I can only speak for myself that all patients who have been implanted for one of my research studies are thoroughly evaluated. I require clear paper documentation of failed adequate trials of antidepressant medication, clarification of diagnostic uncertainty and absence of confounding secondary diagnoses (most frequently substance abuse or personality disorder).

There is clearly a signal which support the use of VNS in some fashion in the short run until we can get more clarity oh which patients are the most likely to respond.

I strongly recommend that CMS not dismiss the use of VNS but instead partner with experienced clinical centers and/or Cyberonics to investigate further the outcomes of TRD when treated with VNS. My specific suggestions:
1. Develop a protocol for supporting the treatment of 500-1000 patients with TRD using specific enrollment criteria. (Consider clearly documented past treatment, diagnosis. Consider excluding PTSD patients)
2. Limit centers for enrollment to 25 sites with adequate research and clinical experience and ability to screen and provide care to at least 20 patients per site.
3. Develop a series of outcome measures that will adequately capture the course of treatment and evidence of change of clinical status. (Include cost of care as an outcome measure.)
4. Two possible means of comparison: compare two years prior to implant to two years post implant for each patient and/or comparison to a matched non-implanted group.

I very strongly hope CMS will understand the devastating nature of TRD, the inadequacies of current interventions and agree to support further investigations into the continued use of this helpful treatment.

Scott T. Aaronson, MD
Director, Clinical Research Programs
Sheppard Pratt Health System
Baltimore, MD

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I concur with the general proposed noncoverage. Much literature was considered and the position is carefully written. CMS may wish to concern three areas of clarification in the final decision memo and NCD.

First, CMS states that treatment-resistant depression is not defined in the DSM, nor is there is any agreed definition elsewhere. Therefore, experience suggests it may be unclear (especially at the ALJ level) exactly what the NCD is not covering. A patient could be said to NOT have TRD within the meaning of the NCD, because the TRD is either undefined or multiple defined. Or for example, VNS could be used for anxiety, insomnia, or another neuropsychiatric condition, always in TRD patients, possibly under a CMS-funded Category B trial for device and implantation, and it would be very unclear whether the NCD applied.

Second, while non-coverage is proposed, if limited coverage is in fact extended in the final NCD, program manual instructions should very clearly instruct contractors how to deal with the Mental Health Treatment Limitation, which flatly and broadly limits payment for non-inpatient "expenses incurred in connection with the treatment of a mental disorder " (SSA 1833). It is difficult to construe VNS/TRD as OTHER than "an expense incurred in connection with a mental disorder." However, while CMS states that contractors shall not independently interpret the SSA, the CMS manual provides no contractor/provider guidance one way or another whether ECT, VNS, etc, fall under the 1833 MHTL. SSA 1833 would also apply to future IDE cohorts whether for routine expenses under Category A (non-inpatient) or routine and/or device expenses in Category B.

Third, the thrust of CMS's analysis is that (a) the statistical difference in VNS-treated patients is very limited, and (b) to the extent there is a difference at all, the extended-cohort trial is not well-controlled. These points are enough to base the analysis on. CMS adds a number of comments regarding the use of neuropsychiatric scales as outcome measures in general ("Assessment of Outcome in Depression.") These comments are actually redundant to the line of argument, that there is simply very limited measurable benefit in VNS-TRD. The only approach to measuring depression, schizophrenia, memory disorders, neurologic head injury impairment, etc, and many other neuropsychiatric disorders is based patient responses and validated scales. There is simply no bright line to be drawn between scales like the Hamilton and any kind of scales (such as pain report) which involved the patient's response in any way. While stating that "reliability and validity determination is both an art and a science" the CMS author is apparently highly dissatisfied with the best results of thousands of efforts over many decades. It would be one thing if the studies had dramatic, favorable results but the author was yet dissatisfied with the scales. That is not the case at all, and the lengthy criticism of the scales, which are internationally accepted, is off point.

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3/5/07
To Whom it May Concern,

I am writing the strongest letter possible in support of VNS technology to treat Refractory Major Depressive Disorder. As the only Board Certified Psychiatrist and Neurosurgeon in the United States I have a unique perspective. I have placed over a hundred VNS systems, including 10 for treatment resistant depression. I have had good results with all those patients. Half of whom have described the VNS to be “life- saving”.

I encourage you not to create a double standard of care; one for “medical” illnesses and the other for “psychiatric”. I think that well designed educational programs for psychiatrists will promote “proper” referrals for VNS implantation. Please do not throw out the baby with the bathwater. This can be a lifesaving treatment for these patients.

Respectfully,
Robert J. Buchanan, M.D.
Director of Functional and Restorative Neurosurgery
The University of Texas Health Science Center at San Antonio
Departments of Neurosurgery, Physiology, and Psychiatry

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I read the staff report and found it outrageously stupid. They seeem to take the position that double blind placebo controlled studies are the only reliably evidence of the efficicy of medical devices and presumably drugs. This is both stupid and junk science. Very few scientific breakthroughs are based on controlled studies. In most fields of science and engineering controlled studies are either impossibly to perform or so impractical that they are rarely used. Relatively little of what we know about our world has actually been derived from controlled studies. They often are difficult to perform, to design in a way that produces useful results and time consuming.

The government should do away with its reliance on junk science and instead rely on all information availably when making important pulic policy deceisions.

Kurt Van Kampen

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As a medical school psychiatrist who specializes in the care of patients with treatment-resistant depression, I strongly urge inclusion of benefits for vagus nerve stimulation therapy (VNS) for depression. WHO currently ranks depression as the third leading cause of disability worldwide. Many people who suffer from depressive illness respond to medication or a combination of medications with psychotherapy, but a sizable minority fail to respond. Among the psychotically depressed, electroconvulsive therapy (ECT) works 90-95% of the time, but in the non-psychotic depressed group, ECT works only about 50% of the time. VNS provides remission in about half of those patients who fail to respond to ECT, and offers persistence of relief that ECT often does not. VNS is an effective therapy for depression, one that should be available to the disabled depressed patients who are beneficiaries of Medicare and Medicaid services. Don't let VNS be reserved only for people with money to pay for it. Provide this life-saving therapy to the people who need it most.

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In the single patient under my care that has the VNS in place, there have been dramatic improvments over a relatively short period of time (2 to 3 months). This patient was slowly sucking-out resources from his insurance with admissions to hospitals for reasons ranging from depression to somatic complaints. He has now been out of the hospitals for the last 3 to 6 months.

THE RESPONSE RATE MAY BE VARIABLE; HOWEVER, FOR THIS PARTICULAR PATIENT, AS FAR AS HE IS CONCERNED, THE RESPONSE RATE IS 100%.

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March 5, 2007

Attention: Beverly A. Lofton, MHA

Dear Ms. Lofton:

I am writing to urge you to consider approval ofMedicare Coverage of Vagus Nerve Stimulationtherapy for Treatment Resistant Depression. Iwrite as both a friend of someone who wants toconsider that treatment and as a clinical socialworker with twenty-four years of experienceworking with people who are depressed. Myclinical experience shows that while many peopleare helped with therapy and anti-depressantmedication, some people continue to struggle. VNSprovides another source of hope for those patients.

Thank you for your attention.

John T. McGuire, MSW, LICSW
Clinical Social Worker

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It seems premature and inappropriate to approve this technology, which has NOT really shown itself to be very effective in the ongoing treatment of Major Depressive Disorder. Please don't give in to pressure from some desperate people and from those who stand to profit from this device. The device itself is expensive. It is supposed to be used in patients who have not responded to 4 different antidepressants for appropriate lengths of time . l can't begin to tell you how many patients I've seen who require 5 or 6 different meds before they respond. I have also seen at least two patients who have the VN stimulator who have NOT gotten any real benefit from it. You're not withholding a needed and proven treatment, you're holding off on approving yet another unnecessary and ineffective treatment.

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Dear Sir or Madam:

I am a physician(neurologist/neurophysiologist) with over 30 years experience in treating patients with intractable epilepsy. I supervise the care of over 80 patients with VNS Therapy systems implanted for control of pharmacoresistant epilepsy. Many of these patients suffer comorbid depression. It is my observation that this comorbid depression responds dramatically to VNS treatment even in patients whose epilepsy remains refractory. I have had experience in programming a single patient with treatment reisitant depression. This patient who required quarterly electroconvulsive therapy treatments was free of the need for such intervention for over a year. I am aware of the pivotal studies of VNS Therapy in treatment resistant depression and I do not understand why CMS came to the conclusion that this effective therapy should not be covered. This decision seems to parallel to the delay in coverage for medicare patients that occurred when deep bain stimulation was approved by the FDA for the treatment of movement diordrs was approved by the FDA. I hope CMS will will reconsider its decision and fund treatment for this group of patients who have largely exhausted all other options. I am not a paid consultant or speaker for Cyberonics and hold no financial interest in its stock. I am currently the PI of a study site for the VNS Therapy Dosage in TRD (D21 Study) study although this study is just being initiated at our site.

Sincerely yours,
Lawrence P. Bernstein, M.D.
Senior Attending Neurologist, ENH
Assistant Professor of Neurology
Northwestern University
Feinberg School of Medicine

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Your study and the APA guidelines and the VNS study all overlook the fact that a LARGE NUMBER of treatment resistant depressions are, in fact bipolar. Eight of my patients have received a vagal nerve stimulator. All have been bipolar. Your use of the DSM IV guidelines for depression means that you are already on the wrong track. ALL of my 8 patients have been bipolar. They alternated between becoming agitated with antidepressants and becoming depressed without them. There was no middle ground. 6 of these have had positive responses as reflected by their initiative, their interests, their ability to get things done, to get out, and to make friends. The other two are significantly improved.

So what is the difference?? If there is any element of agitation, irritability, or racing thoughts (not just on the day you have seen them but in recent weeks), you are likely dealing with a depression with features of both depression and mania. Physicians call this depression since that is the word that patients use, they are treated with antidepressants. They will fail to respond to antidepressants and they will fail to respond to VNS.

One must stabilize the mood first. If they remain in a depression that is converted from the mixed type to a to a "purer depression", which is characterized by vegetation, indifference, generally a lack of irritability, and a lack of motivation that even makes it unlikely they will attempt suicide.

In this setting, we generally cautiously add an antidepressant. If their mood is "brittle" they tend to fly back and forth between a "high energy" depression and a low energy depression. If you are lucky enough to get the right response, that is great and the patient is on the right treatment.

However, many patients are not so lucky and they fare poorly either with the addition of antidepressants and their discontinuation. There is no "right dose" of medication.

My patients have all fallen in this group. They have generally responded to the combination of VNS and mood stabilizers. If antidepressants are kept in the equation to treat a depression with agitated features, they will generally continue to do poorly.

On the other hand, the combination of mood stabilizers and VNS has been successful in my hands. I will be happy to tell you about each of these patients in detail or I will gather them all together for your experts to question in detail.

Without a psychiatrist who has extensive experience treating these patients and who has made their own observations, you will be blind to what I am saying. I suggest you get a true expert in mood disorders, like Fred Goodwin, MD, Charles Nemeroff MD, Stephen Stahl MD, Dr. Akiskal, or Robert Post MD. These individuals know how to make their own observations and thus identify the shortcomings of APA recommendations and the Diagnostic and Statistical Manual.

VNS has made a very significant improvement in 6 of 8 patients and has probably helped the other 2. The Vagal Nerve Stimulation studies have the same limitations in their study design and adequate screening for bipolar.

Before killing a treatment that can improve the quality of life for many people, continue it on a selective basis on patients like the ones I described above. In my patients, MD visits have dropped precipitously and there have been no re-hospitalizations.

I will concede that I have seen many patients with VNS simulators that really had mixed states rather than true depression. This group is doomed to failure.

I would suggest you get one get one of the above experts to review this complex decision before you make a final recommendation. It is my understanding that there was not even a psychiatrist participating in the final decision!! If you get one of the experts above, I will guarantee your final opinion will differ from what you are proposing.

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Treatment Resistant Depression is an insidious disease which destroys lives every day and even ends them. Medicare's decision not to provide reimbursement for VNS treatment for patients who suffer from TRD is DEPLORABLE! DO they provide reimbursement coverage for patients who receive cancer treatments, heart transplants, lung transplants, brain surgery, diabetic treatment? These treatments are not always full proof or give a 100% cure rate or even close to that at times, but they are still recommended to consider or attempt, especially if it means saving a life. Why is our society so blind when it comes to mental illness? . What in God's name is the difference? Illness is illness. Let's just try and save as many people as we can from this monstrous disease and help stop the suffering. Why not get a few people who suffer from TRD to sit on the Medicare decision panel and then listen for an outcome. If you have not walked in our shoes, I don't care how many credentials you hold; you have no authority what so ever to deny us our only chance for hope right now. Shame on all those who voted against this dicision!

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The CMS should take another look at their decision to not cover Vagus Nerve Stimulation Therapy. For some people VNS is a matter of life and death. It can truly save lives and therefore should be reconsidered. At this time it is very important to keep all viable options open for people who have severe treatment resistant depression.

Please take a closer look at how people who have severe treatment resistant depression suffer and how VNS may be the only option for some.

Please do not fall into the trap of not providing equal medical treatment for people who suffer from mental illness.

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The policy draft by CMS to recommend noncoverage of Vagal Nerve Stimulation (VNS)therapy is very concerning and I hope will be modified. As a researcher and clinician who has worked directly with VNS, I have seen the dramatic benefits of this form of therapy for patients with severe depressive conditions who have had prior exhaustive and heroic treatment efforts that were unsuccessful.

Although a definition of treatment resistant depression has not been formally codified, as is the case form many conditions in medicine, practitioners easily recognize the condition of chronic severe depressive symptomatology despite ongoing aggressive treatment efforts. A statement from a report for the AHRQ (2000) is quoted that depresiion "can almost always be treated successfully". At issue here is the "almost".

What is avaialable for the unlucky persons who are not treated successfully with standard therapies? More recent naturalistic data (e.g., STAR-D) suggests that a significant percentage of patients treated for depression do not in fact have successful outcomes even with aggressive efforts.

It suggests an unfair bias against mental disorders that withdrawl of coverage for "approved" treatments of severe depression is being considered. This consideration also suggests a new, higher level of scrutiny than prior treatments have experience.

Rather than not cover VNS, it would be more appropriate to better define the standard treatment resistance that would qualify a patient for this treatment. As to cost, VNS data demonstrates that responders, who prior to VNS had been major healthcare utilizers, have a sustained benefit that has extended for the years that implanted patients have been monitored.

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As President of the National Alliance for the Mentally Ill, I see firsthand the effect on individuals and their families when a family member has treatment resistant depression. The entire family is affected negatively. They struggle to cope with their relative who is chronically depressed.

The members of NAMILA and myself are hopeful that this new treatment will be available for individuals whose depression is not lifted by psypchopharm meds. The negativity and darkness the entire family feels when one family member is chronically depressed is too difficult for any family to endure. With VNS therapy, there is hope for individuals and their families to come out of the malestrom of darkness and experience daily life again. As President of NAMILA, I strongly support the use of VNS therapy and know it must be made available to individuals.

In NAMI, we get acquainted with family members whose relatives eventually commit suicide because nothing has helped. VNS therapy may lessen the suicide rate and allow families to participate comfortably in the world again. As President of NAMI LA, I strongly support the use of VNS therapy for depression. Sharon Dunas MFT

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Medicare should cover this procedure as it does for the Epilepsy treatment. There is enough evidence to support the treatment for depression as well. After a thorough examination by professionals in the field of concern Medicare should accept this as they do any other condition. To consider mental health as a second rate concern is not in the best interest of a human being or the country. Come on Medicare, curb the wasteful spending and help those who need help by accepting your own approved procedures with the monies you save. You might as well get into practice of treating everyone for everything. It's coming, USNHI.

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As a health care provider, I want to comment on the proposed non-coverage of VNS Therapy for TRD. I believe this would indicate gross indifference on the part of CMS with regard to the mental and emotional health of CMS insured. Literature abounds citing the importance of mental and emotional health to overall physical health and well-being. Additionally, the costs of such mental and emotional illness continue to drain health care costs, with few options other than continued medications or ECT. Multiple research studies support what I have seen in my own practice: the majority of patients who receive VNS therapy will experience a relatively minimal side-effect profile, an improved level of alertness, a sustained response to VNS therapy, improved memory, thinking and concentration, and absolutely no interactions with medications; additionally, some have the added benefit of being able to reduce pharmacotherapeutic regimens. Costs for VNS Therapy range from $25-30,000 for VNS implant and parameter management, all for therapy that could last from 5-10 years. Per the HAMD24 Remission and Response rates, 17% of patients with TRD were free of depressie symptoms; 32% of patients with TRD achieved a clinical response. Of these 32%, 70% of patients who responded acutely maintained their response.

Contrast these benefits with electroconvulsive therapy, historically covered by CMS. ECT has a high side-effect profile; patients will often experience diminished alertness, progressive memory loss, sustained diminution of memory, thinking and concentration, as well as a relapse rate of 70% in the first year. ECT costs approx $2000 per session and typically 8 sessions are needed to initiate therapy. Given the high relapse rate, ECT would need to be repeated over subsequent years. If repeated over 3 years, the above side-effects would be amplified, and the costs would be $48,000. Nearly twice as much as VNS therapy for 5-10 years.

Additionally, for the some 2000 patients implanted with VNS for TRD thus far, some 1000 of these have been covered by Medicare. This precedent has been set and will now make the non-coverage of future TRD patients particularly objectionable, if not unethical. Patients whose mental, emotional and thus overall physical health status stands to improve substantially from a treatment proven safe and efficacious should be afforded this opportunity.

The effects of TRD and benefits of improved overall health are innumerable and should not need to be ennumerated here. Please revise your non-coverage policy to make VNS therapy a potential option to individuals with TRD.

Thank you. Christi Ledo

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I am neurosurgeon certified by the American Board of Neurological Surgery. I am licensed by and practicing in the State of Illinois where I am an Associate Professor of Neurosurgery at the Feinberg School of Medicine of Northwestern University. I practice at Evanston Hospital in Evanston, Illinois. I have a long standing subspecialty interest in the field of functional neurosurgery. I am a member of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS). I am also a member of the Board of Directors of the American Association of Neurological Surgeons. I have no association with Cyberonics. I have not participated as an investigator or reviewer of the device being considered although I do plan to participate in one of their upcoming studies (not as a principle investigator). Neither I nor my family directly own stock in Cyberonics nor are we directors on any of its Boards.

I would like to voice my strong support for the use of vagal nerve stimulation (VNS) for treatment resistant depression (TRD) in patients who are deemed appropriate candidates for this device.

Vagal nerve stimulation (VNS) has proven to be a very safe, effective and useful procedure in the treatment of intractable epilepsy and I likewise believe that it will be shown to be effective and useful in the treatment of resistant depression (TRD).

Since vagal nerve stimulation for epilepsy was approved by the FDA, thousands of patients have undergone surgery for implantation of this device. It is widely recognized by the neurologists who care for these patients after surgery that many of the patients who also had depression showed a marked improvement in their mood, independent of any improvement in their seizures.

The published studies on the effectiveness of VNS for TRD demonstrate an efficacy greater or equal to the effect of additional medication. For example, one study looking at 12 month outcomes showed a significant response in 27% of patients and a remission in 20%. Although these studies have been sponsored by the company that makes the device, their findings are nevertheless important to our understanding of the efficacy of the device.

I hope that the post-approval studies of VSN for TRD will add to our understanding of the benefits and limits of this device and its place in the treatment of this dreadful disorder. These studies cannot be performed without some sort of compensation to physicians and hospitals from CMS and other third party payors. I strongly believe that these studies will show that the overall cost of care for these patients will be lower in the group who have the device implanted compared to those who do not have the device. One will never know unless the study is performed.

I am excited by the ongoing collaboration with our colleagues in psychiatry for the treatment of depression with appropriate surgical intervention.

Again, thank you for considering my views on this issue.

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The report was thorough but not thorough enough. The only two methods available to patients that have 10 or more years of treatment resistant depression are ECT and VNS. I find it unethical to force a patient to have ECT when it is not indicated. Such is the case of one of my patients. VNS was rejected by the insurance and because TRD (treatment resistant depression) is a life threatening condition and after years of avoiding hopitalization the patient is now in the hospital and forced to have ECT for her TRD. This patient has a baseline of cognitive impairment not solely due to the patients depression. Exposure to ECT can increase the patients cognitive impairment chronicaly. My question to you is this ethical? Who is going to asume responsability? Here is a review of ECT by the NIMH:Electroconvulsive Therapy

National Institutes of Health Consensus Development Conference Statement June 10-12, 1985

This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/.

This statement was originally published as: Electroconvulsive Therapy. NIH Consens Statement 1985 Jun 10-12; 5(11):1-23.

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Electroconvulsive Therapy. NIH Consens Statement Online 1985 Jun 10-12 [cited year month day]; 5(11):1-23.

Introduction

Electroconvulsive therapy (ECT) is a treatment for severe mental illness in which a brief application of electric stimulus is used to produce a generalized seizure. In the United States in the 1940s and 1950s, the treatment was often administered to the most severely disturbed patients residing in large mental institutions. As often occurs with new therapies, ECT was used for a variety of disorders, frequently in high doses and for long periods. Many of these efforts proved ineffective, and some even harmful. Moreover, its use as a means of managing unruly patients, for whom other treatments were not then available, contributed to the perception of ECT as an abusive instrument of behavioral control for patients in mental institutions for the chronically ill. With the introduction of effective psychopharmacologic medications and the development of judicial and regulatory restrictions, the use of ECT has waned.

The treatment is now used primarily in general hospital psychiatric units and in psychiatric hospitals. A National Institute of Mental Health hospital survey estimated that 33,384 patients admitted to hospital psychiatric services during 1980 were treated with ECT, representing approximately 2.4 percent of all psychiatric admissions.

Although ECT has been in use for more than 45 years, there is continuing controversy concerning the mental disorders for which ECT is indicated, its efficacy in their treatment, the optimal methods of administration, possible complications, and the extent of its usage in various settings. These issues have contributed to concerns about the potential for misuse and abuse of ECT and to desires to ensure the protection of patient's rights. At the same time, there is concern that the curtailment of ECT use in response to public opinion and regulation may deprive certain patients of a potentially effective treatment.

In recent decades, researchers intensified efforts to establish the effectiveness of ECT and its indications, understand its mechanism of action, clarify the extent of adverse effects, and determine optimum treatment technique. Despite recent research efforts yielding substantial information, permitting professional and public evaluation of the safety and efficacy of ECT, the investigation of ECT has not generally been in the mainstream of mental health research.

To help resolve questions surrounding these issues, the National Institutes of Health in conjunction with the National Institute of Mental Health convened a Consensus Development Conference on Electroconvulsive Therapy on June 10-12, 1985. For 1 1/2 days, experts in the field presented their findings, and an audience, including health professionals, former patients, and other interested persons, discussed the issues. A consensus panel representing psychiatry, psychology, neurology, psychopharmacology, epidemiology, law, and the general public considered the scientific evidence and agreed on answers to the following questions:

What is the evidence that ECT is effective for patients with specific mental disorders? What are the risks and adverse effects of ECT? What factors should be considered by the physician and patient in determining if and when ECT would be an appropriate treatment? How should ECT be administered to maximize benefits and minimize risks? What are the directions for future research? What Is the Evidence That ECT Is Effective for Patients With Specific Mental Disorders?Published controlled studies of ECT permit evaluation of its short-term efficacy in severe major depressions (delusional and endogenous), in acute mania, and in certain schizophrenic syndromes. The available controlled clinical trials do not extend beyond the treatment of the acute episode (i.e., about 4 weeks). These studies are difficult to compare because they have used differing diagnostic systems and research designs. Further, they have measured outcome only in terms of symptom reduction, not the quality of life and social functioning.

Depression
Studies of ECT in depression have used various control conditions for comparison, including "sham" ECT (e.g., all of the elements of the ECT procedure except the electric stimulus), tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI), combinations of antidepressants and neuroleptics, and placebos. The efficacy of ECT has been established most convincingly in the treatment of delusional and severe endogenous depressions, which make up a clinically important minority of depressive disorders. Some studies find ECT to be of at least equal efficacy to medication treatments, and others find ECT to be superior to medication. Not a single controlled study has shown another form of treatment to be superior to ECT in the short-term management of severe depressions. It must be noted, however, that those studies that found ECT to be superior to medication were not designed to study the persistence of this advantage of ECT beyond the short term. Moreover, the available evidence suggests that relapse rates in the year following ECT are likely to be high unless maintenance antidepressant medications are subsequently prescribed. Several studies suggest that ECT reduces symptoms in severely depressed patients who previously have not responded to adequate trials of antidepressant medication. The literature also indicates that ECT, when compared with antidepressants, has a more rapid onset of action.

Delusional Depression
ECT is highly effective in the treatment of delusional depression. It is superior to either antidepressants or neuroleptics used alone and is at least as effective as the combination of antidepressants and neuroleptics. ECT is often effective in patients who have previously failed to respond to medication. The duration of therapeutic effect beyond the initial acute episode is not clear.

Endogenous/Melancholic Depression
The severe endogenous/melancholic depressions are characterized by early morning awakening, marked weight loss, psychomotor retardation and/or agitation, diurnal variation, and lack of reactivity. ECT is at least as effective as TCA and more effective than sham ECT in the short-term treatment of these severe endogenous/melancholic depressions. ECT appears to be more effective than MAOI in the treatment of severe depressions, but available studies have generally used relatively low MAO doses. There is evidence for the efficacy of ECT in those endogenous depressives who have not responded to an adequate trial of antidepressants. The long-term efficacy of ECT with endogenously depressed patients is not known.

Other Depression
The majority of depressed persons encountered in medical and psychiatric settings do not have the severe endogenous/melancholic or delusional depressions described above. ECT is not effective for patients with milder depressions, i.e., dysthymic disorder (neurotic depression) and adjustment disorder with depressed mood. Patients with major depression that is nonendogenous/nonmelancholic have not yet been extensively studied. Because of this, it is unclear whether their response to ECT would be more like those with dysthymic disorders or those with endogenous/melancholic features.

Acute Manic Episode
ECT and lithium appear to be equally effective for acute mania, and either is superior to hospitalization without somatic therapy. A treatment regimen in which ECT is used for the acute episode, followed by lithium maintenance, does not appear to be associated with an increased risk of early relapse compared with lithium treatment alone.

Schizophrenia
Neuroleptics are the first line of treatment for schizophrenia. The evidence for the efficacy of ECT in schizophrenia is not compelling but is strongest for those schizophrenic patients with a shorter duration of illness, a more acute onset, and more intense affective symptoms. ECT has not been useful in chronically ill schizophrenic patients. Although ECT is frequently advocated for treatment of patients with schizophreniform psychoses, schizoaffective disorders, and catatonia, there are no adequate controlled studies to document its usefulness for these disorders.

Other Disorders
There are no controlled studies supporting the efficacy of ECT for any conditions other than those designated above (i.e., delusional and severe endogenous depression, acute mania, and certain schizophrenic syndromes).

What Are the Risks and Adverse Effects of ECT? To maximize the benefits of ECT and minimize the risks, it is essential that the patient's illness be correctly diagnosed, that ECT be administered only for appropriate indications, and that the risks and adverse effects be weighed against the risks of alternative treatments. Risks and adverse effects of ECT can be divided into two categories: (1) Those medical complications that can be substantially reduced by the use of appropriately trained staff, best equipment, and best methods of administration and (2) those side effects, such as spotty but persistent memory loss and transient posttreatment confusion, that can be expected even when an optimal treatment approach is used. In this report, we will focus on the risks still present with adequate treatment techniques.

In the early days of ECT, mortality was a significant problem. The commonly quoted overall mortality rate in the first few decades was 0.1 percent or 1 per 1,000. Over the years, safer methods of administration have been developed, including the use of short-acting anesthetics, muscle relaxants, and adequate oxygenation. Present mortality is very low. In the least favorable recent series reported, there were 2.9 deaths per 10,000 patients, another series, 4.5 deaths per 100,000 treatments were reported. Overall, the risk is not different from that associated with the use of short-acting barbiturate anesthetics. The risk of death from anesthesia, although very small, is present and should be considered when evaluating the setting for performing ECT.

In the past, up to 40 percent of patients suffered from various complications, the most common being vertebral compression fractures. With present techniques, these risks have been virtually eliminated. In one recent study of almost 25,000 treatments, a complication rate of 1 per 1,300 to 1,400 treatments was found. These included laryngospasm, circulatory insufficiency, tooth damage, vertebral compression fractures, status epilepticus, peripheral nerve palsy, skin burns, and prolonged apnea.

During the few minutes following the stimulus, profound and potentially dangerous systemic changes occur. First, there may be transient hypotension from bradycardia caused by central vagal stimulation. This may be followed by sinus tachycardia and also sympathetic hyperactivity that leads to a rise in blood pressure, a response that may be more severe in patients with essential hypertension. Intracranial pressure increases during the seizure. Additionally, cardiac arrhythmias during this time are not uncommon (but usually subside without sequelae). Thus, certain patient groups that would be adversely affected by these manifestations are at increased risk.

There are two categories of central nervous system effects: The immediate consequences of the ECT seizure and the more enduring effects, both of which are affected by the treatment course. Immediately after awakening from the treatment, the patient experiences confusion, transient memory loss, and headache. The time it takes to recover clear consciousness, which may be from minutes to several hours, varies depending on individual differences in response, the type of ECT administered, the spacing and number of treatments given, and the age of the patient.

The severity of this acute confusional state is greatest after bilateral sine wave treatment and least when nondominant unilateral pulsed ECT is administered. Severity also appears to be increased by longer seizure duration, close spacing of the treatments, increasing dosage of electrical stimulation, and each additional treatment.

Depressive disorders are characterized by cognitive deficits that may be difficult to differentiate from those due to ECT. It is, however, well established that ECT produces memory deficits. Deficits in memory function, which have been demonstrated objectively and repeatedly, persist after the termination of a normal course of ECT. Severity of the deficit is related to the number of treatments, type of electrode placement, and nature of the electric stimulus. Greater deficit occurs from bilateral than from unilateral placement. Sine wave current has been found to impair memory more than pulsed current.

The ability to learn and retain new information is adversely affected for a time following the administration of ECT; several weeks after its termination, however, this ability typically returns to normal. There is also objective evidence, based on neuropsychological testing, of loss of memory for a few weeks surrounding the treatment; such objective tests have not firmly established persistent or permanent deficits for a more extensive period, particularly for unilateral ECT. However, research conducted as long as 3 years after treatment has found that many patients report that their memory was not as good as it was prior to the treatment. They report particular difficulties for events that occurred on average 6 months before ECT (retrograde amnesia) and on average 2 months after the treatment (anterograde amnesia). Because there is also a wide difference in individual perception of the memory deficit, the subjective loss can be extremely distressing to some and of little concern to others.

There are other possible adverse effects from ECT. Some patients perceive ECT as a terrifying experience; some regard it as an abusive invasion of personal autonomy; some experience a sense of shame because of the social stigma they associate with ECT; and some report extreme distress from persistent memory deficits. The panel heard eloquent testimony of these attitudes from former patients who had been treated with ECT. It is clear, however, that these attitudes are not shared by all ECT patients. The panel also heard moving testimony from former patients who regarded ECT as a wholly beneficial and lifesaving experience. There are insufficient systematic studies to permit any definitive assessment of the prevalence of these various perceptions among ECT patients.

Numerous ECT studies have been conducted with animal models. Many of these suffer from methodological shortcomings. In studies that have been controlled for fixation artifacts, hypoxia, and other methodological problems, neuronal cell death has not been detected. Cerebral vasospasm and alterations in capillary permeability are of short duration and of insufficient magnitude to lead to neuronal cell death. The precise mechanism of the anterograde and retrograde memory deficit has not been established; it may represent alterations in neuronal function that are not detectable with present methods. Computerized axial tomography (CAT) studies of patients who have had ECT are very preliminary and open to alternative interpretations. Definitive studies of in vivo brain metabolism with positron emission tomography (PET) and studies of tissue changes detectable by magnetic resonance imaging (MRI) remain to be done.

What Factors Should Be Considered by the Physician and Patient in Determining If and When ECT Would Be an Appropriate Treatment?
The consideration of ECT is most appropriate in those conditions for which efficacy has been established: Delusional and severe endogenous depressions, acute mania, and certain schizophrenic syndromes. ECT should rarely be considered for other psychiatric conditions. The decision whether to offer ECT to an individual patient should be based on a complex consideration of advantages and disadvantages for ECT and for each treatment alternative. Whether to use ECT should be based on a thorough review of severity of the patient's illness, medical indications and contraindications, and nonresponsiveness to other treatments. It should be emphasized that for certain patients with very specific and narrow indications, ECT may be the only effective treatment available. In certain circumstances of acute risk to life or of medical status incompatible with the use of other effective treatments, ECT may be the first treatment.

The panel is concerned that ECT only be administered for the benefit of individual patients. Institutional factors (such as financial pressures created by prospective systems or staff convenience) should play no role in the decision to administer ECT.

Severity
Given a diagnosis for which the efficacy of ECT has been established, the immediate risk of suicide (when not manageable by other means) is a clear indication for the consideration of ECT. Acute manic episode especially when characterized by clouded sensorium, dehydration, extreme psychomotor agitation, high risk for serious medical complications or death through exhaustion, and nonresponse to pharmacological interventions are also clear indications for ECT. The severe and unremitting nature of the patient's emotional suffering, or extreme incapacitation, are also important considerations.

Medical Indications and Contraindications
The patient's medical status is often the determining consideration in the use of ECT. ECT may be necessary when the patient has medical conditions that preclude the use of TCA, MAOI, lithium, and neuroleptics. ECT should be considered in patients with severe depression or psychosis during the first trimester of pregnancy. Conversely, ECT is contraindicated for increased intracranial pressure, while space-occupying lesions in the brain, a recent history of myocardial infarction, and large aneurysms are relative contraindications for ECT. A personal history of nonresponsiveness to, or debilitating side effects (medical or psychological) from, ECT are also possible contraindications.

Nonresponsiveness to Other Treatments
ECT should be considered when alternative pharmacological and/or psychotherapeutic treatments have been given an adequate trial without efficacious response. When a patient is nonresponsive to other treatments, factors such as severity of the illness, its natural course, and the risk of other treatments worsening the course (as, for example, antidepressant medications precipitating a manic episode) need to be taken into account.

Informed Consent
When the physician has determined that clinical indications justify the administration of ECT, the law requires, and medical ethics demand, that the patient's freedom to accept or refuse the treatment be fully honored. An ongoing consultative process should take place. In this process, the physician must make clear to the patient the nature of the options available and the fact that the patient is entitled to choose among those options.

No uniform "shopping list" can be drawn up regarding the matters that should be discussed by patient and physician to assure a fully informed consent. They should discuss the character of the procedure, its possible risks and benefits (including full acknowledgement of posttreatment confusion, memory dysfunction, and other attendant uncertainties), and the alternative treatment options (including the option of no treatment at all). Special individual needs may also be relevant to some patients, for example, a personal situation that requires rapid remission to facilitate return to work and to reduce family disruption. In all matters, the patient should not be inundated with technical detail; the technical issues should be translated into terms meaningful and accessible to the patient.

It is not easy to achieve this ideal of "informed consent" in any aspect of medical practice; and there are special difficulties that arise regarding the administration of ECT. In particular, the patients for whom this procedure is medically appropriate may be suffering from a severe psychiatric illness that, although not impairing their legal competency to consent, may nonetheless cloud judgment in fully weighing all of the available options. Such judgmental distortion does not justify disregarding the patient's choices; rather it makes it all the more important that the physician strive to identify and clarify the options that the patient alone is entitled to exercise.

The consent given by the patient at the outset of treatment should not be the final exchange on this issue but should be reexamined with the patient repeatedly throughout the course of the treatment. These periodic reviews should be initiated by the physician and not depend on patient initiative to "rescind" consent.

There are several reasons for this repeated consenting procedure: because of the relatively rapid therapeutic effect of the procedure itself, the patient after initial treatments is likely to have enhanced judgmental capacities; the risks of adverse effects increase with repeated treatments, so that the question of continued treatment presents a possibly changed risk/benefit assessment for the patient; and because of the short-term memory deficits that accompany each administration of ECT, the patient's recollection of the prior consenting transaction might itself be impaired, so that repeated consultations reiterating the patient's treatment options are important to protect the patient's sense of autonomy throughout the treatment process. Moreover, if the patient agrees, the family should be involved in each step of this consultative process.

In a small minority of cases, a patient will lack adequate legal capacity to consent to the proposed procedure. In such cases, timely court proceedings are necessary if treatment is to be provided. Legislation in a few states dictates that ECT may in no circumstance be provided to an involuntarily committed patient. The panel believes that such absolute bans are unduly restrictive and make treatment impossible for patients who might obtain more benefit, at acceptable levels of risk, from ECT than from alternative treatments.

It may be desirable for physicians with patients for whom the prospect of ECT is a foreseeable but not immediate possibility to discuss this in advance with the patient when his or her judgment appears least compromised by the underlying disease process. Such advance discussion would serve as a nonbinding guide both to the patient and physician and would be another means to enhance the patient's autonomous choice in weighing the risks and benefits of this procedure and its alternatives.

How Should ECT Be Administered To Maximize Benefits and Minimize Risks? Once the patient and the physician have decided that ECT may be indicated, the patient should undergo a pretreatment medical examination that includes a history, physical, neurologic examination, EKG, and laboratory tests. Medications that affect the seizure threshold should be noted and decreased or discontinued when clinically feasible. MAOI should be discontinued 2 weeks before treatment, and patients should be essentially lithium-free. Severe hypertension should be controlled before beginning treatment. Because some patients with compromised cardiovascular status will be receiving ECT, cardiac conditions should be evaluated and monitored closely. Educating the patient and the family through discussion and written and/or audiovisual material describing the procedure is necessary prior to obtaining written informed consent.

An area should be designated for the administration of ECT and for supervised medical recovery from the treatment. This area should have appropriate health care professionals available and should include equipment and medications that could be used in the event of cardiopulmonary or other complications from the procedure.

A health professional specifically trained and certified in the use of brief anesthetic procedures should administer the anesthesia. The treatment team should include nursing personnel trained in ECT procedures and recovery.

Typically, ECT is administered as follows: the treatment is given in the early morning after an 8- to 12-hour period of fasting. Atropine or another anticholinergic agent is given prior to the treatment. An intravenous line is placed in a peripheral vein, and access to this vein is maintained until the patient is fully recovered. The anesthetic methohexital is given first, followed by succinylcholine for muscle relaxation. Ventilatory assistance is provided with a positive pressure bag using 100 percent oxygen. The EKG, blood pressure, and pulse rate should be monitored throughout the procedure. Stimulus electrodes are placed either bifrontotemporally (bilateral) or with one electrode placed frontotemporally and the second electrode placed on the ipsilateral side (unilateral). Bilateral ECT may be more effective in certain patients or conditions. It has been established, however, that unilateral ECT, particularly on the nondominant side, is associated with a shorter confusional period and fewer memory deficits. Also, a brief pulse stimulus is associated with fewer cognitive defects than the traditional sine wave stimulus. Seizure threshold varies greatly among patients and may be difficult to determine; nevertheless the lowest amount of electrical energy to induce an adequate seizure should be used. Seizure monitoring is necessary and may be accomplished by an EEG or by the "cuff" technique. In this technique, a blood pressure cuff is placed on an arm or leg and is inflated above systolic pressure prior to the injection of a muscle relaxing agent. In unilateral ECT, the cuff should be on the same side as the electrodes to ensure that a bilateral seizure occurred.

The number of treatments in a course of therapy varies. Six to twelve treatments are usually effective. In the United States, the usual frequency is three times weekly; in the United Kingdom, the standard practice is two treatments weekly. Regressive ECT (a large number of treatments given within a short period for the purpose of achieving a persistent organic brain syndrome) is no longer an acceptable treatment form. Multiple-monitored ECT (several seizures during a single treatment session) has not been demonstrated to be sufficiently effective to be recommended. There are no controlled studies on the periodic use of ECT after remission of the acute episode or as a maintenance regimen to prevent recurrence of new episodes. Following ECT, most depressed patients should be continued on antidepressant medication or lithium to reduce relapse.

The panel is concerned that there are only limited data on the manner and extent of ECT administration in the United States and on the training of personnel involved in it. A national survey should be undertaken to assemble basic facts about the status of ECT treatment.

Medical school curricula should include education in the use of ECT. Psychiatric residency programs should include complete ECT training: indications, contraindications, risks, clinical management, informed consent, and evaluation of outcome. The American Board of Psychiatry and Neurology should include questions about ECT in its oral and written examinations.

The panel believes it is imperative that appropriate mechanisms be established to ensure proper standards and monitoring of ECT. Hospitals and centers using ECT should establish review committees modeled on other medical-surgical review committees and should formulate rules and regulations to govern the privileging of physicians giving the treatments. Stringent peer review consistent with Joint Commission for the Accreditation of Hospitals' standards should monitor ongoing utilization of ECT. Periodic inspection of the equipment is also essential. As experience accumulates, consideration should be given to the adequacy of existing monitoring and review mechanisms.

What Are the Directions for Future Research? ECT has been underinvestigated in the past. Among the most important immediate research tasks are:

Initiation of a national survey to assemble the basic facts about the manner and extent of ECT use, as well as studies of patient attitudes and responses to ECT. Better understanding of negative, positive, and indifferent responses should result in improved treatment practices. Identification of the biological mechanisms underlying the therapeutic effects of ECT and the memory deficits resulting from the treatment. Better delineation of the long-term effects of ECT on the course of affective illnesses and cognitive functions, including clarification of the duration of ECT's therapeutic effectiveness. Precise determination of the mode of electrode placement (unilateral versus bilateral) and the stimulus parameters (form and intensity) that maximize efficacy and minimize cognitive impairment. Identification of patient subgroups or types for whom ECT is particularly beneficial or toxic.

Conclusion
Electroconvulsive therapy is the most controversial treatment in psychiatry. The nature of the treatment itself, its history of abuse, unfavorable media presentations, compelling testimony of former patients, special attention by the legal system, uneven distribution of ECT use among practitioners and facilities, and uneven access by patients all contribute to the controversial context in which the consensus panel has approached its task.

The panel has found that ECT is demonstrably effective for a narrow range of severe psychiatric disorders in a limited number of diagnostic categories: delusional and severe endogenous depression and manic and certain schizophrenic syndromes. There are, however, significant side effects, especially acute confusional states and persistent memory deficits for events during the months surrounding the ECT treatment. Proper administration of ECT can reduce potential side effects while still providing for adequate therapeutic effects.

The physician's decision to offer ECT to a patient and the patient's decision to accept it should be based on a complex consideration of advantages and disadvantages of ECT compared with alternative treatments. An ongoing consultative process, requiring time and energy on the part of both patient and physician, should occur.

Much additional research is needed into the basic mechanisms by which ECT exerts its therapeutic effects. Studies are also needed to better identify subgroups for whom the treatment is particularly beneficial or toxic and to refine techniques to maximize efficacy and minimize side effects. A national survey should be conducted on the manner and extent of ECT use in the United States.

These recommendations reflect the consensus of the panel. We have been careful to narrowly delineate when and how, in our judgment, ECT should be administered. To prevent misapplication and abuse, it is essential that appropriate mechanisms be established to ensure proper standards and monitoring of ECT.

Consensus Development Panel
Robert M. Rose, M.D.
Panel Chairman
Professor and Chairman
Department of Psychiatry and Behavioral Sciences
University of Texas Medical Branch
Galveston, Texas
Robert A. Burt, J.D.
Southmayd Professor of Law
Yale Law School
Yale University
New Haven, Connecticut
Paula J. Clayton, M.D
Professor and Head
Department of Psychiatry
University of Minnesota
Minneapolis, Minnesota
Allen Frances, M.D.
Professor of Psychiatry
Cornell University Medical College
New York, New York
Arnold J. Friedhoff, M.D.
Director of Millhauser Laboratories
Professor of Psychiatry
New York University College of Medicine
New York, New York
Kay Redfield Jamison, Ph.D.
Associate Professor and Director
Affective Disorders Clinic
Department of Psychiatry
University of California at Los Angeles School of Medicine
Los Angeles, California
David S. Janowsky, M.D.
Professor of Psychiatry
Director
Mental Health Clinical Research Center
University of California at San Diego
Staff Physician
San Diego Veterans Administration Medical Center
La Jolla, California
Jonathan Leff
Editorial Consultant
Retired Director
Consumer Reports Books
South Hero, Vermont
Ilo E. Leppik, M.D.
Associate Professor of Neurology
University of Minnesota
St. Paul Ramsey Medical Center
St. Paul, Minnesota
Douglas M. McNair, Ph.D.
Professor and Director
Clinical Psychopharmacology Laboratory
Clinical Psychology Ph.D. Program
Boston University
Boston, Massachusetts
Leonard I. Stein, M.D.
Professor of Psychiatry
University of Wisconsin Medical School
Medical Director
Dane County Mental Health Center
Madison, Wisconsin
Verner Stillner, M.D., M.P.H.
Medical Director
Charter Ridge Hospital
Professor of Psychiatry
University of Kentucky
Lexington, Kentucky
Myrna M. Weissman, Ph.D.
Professor of Psychiatry and Epidemiology
Director
Depression Research Unit
Department of Psychology
Yale University School of Medicine
New Haven, Connecticut
Robert P. Withrow, M.D., M.P.H.
Associate Director
Mental Health Department
Director of Inpatient Unit
Fresno Community Hospital and Medical Center
Assistant Clinical Professor
Department of Psychiatry
University of California at San Francisco School of Medicine
Fresno, California
Speakers
Richard Abrams, M.D.
"Clinical Strategies in Choice and Timing of ECT"
Professor and Vice Chairman
Department of Psychiatry
University of Health Sciences and Chicago Medical School
North Chicago, Illinois
Sydney Brandon, M.D., F.R.C.Psych.
"Efficacy in Depression: Controlled Trials"
Foundation Professor of Psychiatry
Head of Department of Psychiatry
University of Leicester
Clinical Sciences Building
Royal Infirmary
Leicester ENGLAND
Peter R. Breggin, M.D.
"Neuropathology and Cognitive Dysfunction from ECT"
Psychiatrist and Director
Center for the Study of Psychiatry
Bethesda, Maryland
Jan Fawcett, M.D.
"Efficacy in Depression: ECT Versus Antidepressants"
Professor and Chairman
Department of Psychiatry
Rush-Presbyterian-St. Lukes Medical Center
Chicago, Illinois
Max Fink, M.D.
"Convulsive Therapy: How It Evolved"
Professor of Psychiatry
State University of New York at Stony Brook School of Medicine
St. James, New York
Christopher Freeman, M.B., Ch.B., M.R.C.Psych., M.Phil
"Patients' Attitudes Toward ECT"
Consultant Psychiatrist
University of Edinburgh
Royal Edinburgh Hospital
EdinburghSCOTLAND
Gerald L. Klerman, M.D.
"The Use of Somatic Treatments for Psychiatric Illnesses"
Professor of Psychiatry
Harvard Medical School
Director of Psychiatric Research
Department of Psychiatry
Massachusetts General Hospital
Boston, Massachusetts
Bernard Lerer, M.D.
"ECT: Possible Mechanisms of Action"
Jerusalem Mental Health Center
JerusalemISRAEL
Agnete Mouritzen Dam, M.D., Ph.D.
"Quantitative Neuropathology in Electrically Induced Generalized Convulsions"
Neurologist and Research Assistant
Neurological Laboratory
University Hospital Hvidovre
VirumDENMARK
John Parry, J.D.
"Legal Parameters of Informed Consent for ECT Administered to Mentally Disabled Persons"
Staff Director
Commission on the Mentally Disabled
Editor
Mental and Physical Disability Law Reporter of the American Bar Association
Washington, D.C.
Ferris N. Pitts, Jr., M.D.
"General Technique of ECT"
Professor of Psychiatry
Department of Psychiatry and Behavioral Sciences
University of Southern California School of Medicine
Los Angeles, California
Trevor R. P. Price, M.D.
"Systemic Effects of ECT"
Associate Professor of Psychiatry and Medicine
Dartmouth Medical School
Hanover, New Hampshire
Loren H. Roth, M.D., M.P.H.
"Data on Informed Consent for ECT"
Professor of Psychiatry
Chief of Adult Clinical Services
Western Psychiatric Institute and Clinic
University of Pittsburgh
Pittsburgh, Pennsylvania
David J. Rothman, Ph.D.
"ECT: The Historical, Social, and Professional Sources of the Controversy"
Bernard Schoenberg
Professor of Social Medicine
Center for the Study of Society and Medicine
Columbia University College of Physicians and Surgeons
New York, New York
Harold A. Sackeim, Ph.D.
"Acute Cognitive Side Effects of ECT"
Associate Professor of Psychology
New York University
Research Scientist and Deputy Chief
Department of Biological Psychiatry
New York State Psychiatric Institute
New York, New York
Joyce G. Small, M.D.
"Efficacy of ECT in Schizophrenia, Mania, and Other Disorders"
Professor of Psychiatry
Indiana University School of Medicine
Larue D. Carter Memorial Hospital
Indianapolis, Indiana
Larry R. Squire, Ph.D.
"The Question of Long-Term Effects"
Professor of Psychiatry and Research Career
Scientist
Veterans Administration Medical Center
Department of Psychiatry
University of California at San Diego School of Medicine
San Diego, California
James W. Thompson, M.D., M.P.H.
"Utilization of ECT in U.S. Psychiatric Facilities, 1970 to 1980"
Chief
Service System and Economics Research Branch
Division of Biometry and Epidemiology
National Institute of Mental Health
Rockville, Maryland
Richard D. Weiner, M.D., Ph.D.
"Electrical Dosage, Stimulus Parameters, and Electrode Placement"
Associate Professor of Psychiatry
Duke University Medical Center
Psychiatry Service
Durham Veterans Administration Medical Center
Durham, North Carolina
Planning Committee
Robert M. Rose, M.D.
Panel Chairman
Professor and Chairman
Department of Psychiatry and Behavioral Sciences
University of Texas Medical Branch
Galveston, Texas
Richard Abrams, M.D.
Professor and Vice Chairman
Department of Psychiatry
University of Health Sciences and Chicago Medical School
North Chicago, Illinois
Michael J. Bernstein
Director of Communications
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Jack D. Blaine, M.D.
National Institute of Mental Health
Coordinator
Research Psychiatrist
Affective Disorders Section
Pharmacologic and Somatic Treatments Research Branch
National Institute of Mental Health
Rockville, Maryland
Susan M. Clark
Office of Medical Applications of Research
Coordinator
Social Science Analyst
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Alan J. Gelenberg, M.D.
Psychiatrist-in-Chief
The Arbour
Chief of Special Studies
Massachusetts General Hospital
Associate Professor
Harvard Medical School
Jamaica Plain, Massachusetts
Michael S. Gluck, D.Sc., P.E.
Chief
Anesthesiology and Respiratory Therapy Devices Branch
Food and Drug Administration
Silver Spring, Maryland
Myrle Kahn
Public Information Specialist
Public Communications Branch
National Institute of Mental Health
Rockville, Maryland
Harold Alan Pincus, M.D.
Special Assistant to the Director
National Institute of Mental Health
Rockville, Maryland
William Z. Potter, M.D., Ph.D.
Chief
Section on Clinical Psychopharmacology
Laboratory of Clinical Science
National Institute of Mental Health
Rockville, Maryland
Norman Rosenberg, J.D.
Director
Mental Health Law Project
Washington, D.C.
Harold A. Sackeim, Ph.D.
Associate Professor of Psychology
New York University
Research Scientist and Deputy Chief
Department of Biological Psychiatry
New York State Psychiatric Institute
New York, New York
Richard D. Weiner, M.D., Ph.D.
Associate Professor of Psychiatry
Duke University Medical Center
Psychiatry Service
Durham Veterans Administration Medical Center
Durham, North Carolina
Sponsors
National Institute of Mental Health
Shervert Frazier, M.D.
Director Office of Medical Applications of Research, NIH
Itzhak Jacoby, Ph.D. Acting Director

VNS is a non pharmacological treatment to depressiona and it should be compared to other non pharmacological treatments such as ECT. My question to you is how do you define treatment resistant to major depression when you apply ECT? and what are the side effects of VNS versus ECT?I noticed that some of your referenced mentioned Blue Cross and Blue Shield evaluations. Is Blue Cross and Blue Shield going to be liable for either my patients death or my patients cognitive impairment that would remove the patient from being a productive contributor to society??As a physician I am liable for life and death decisions. Why can't an insurance who provides care to patients with life or death conditions can't they be also liable for denying adequate treatment?
Sincerely
Marjorie Hawkins MD
Lighthouse Clinic
2577 North Downer Avenue
Milwaukee, WI 53211

Less

I am a private psychiatrist in Bellevue, WA with no financial connection to cyberonics. My practice is mostly filled with difficult to treat mood disorders. I read with sadness & anger (but not surprise) medicare's proposal to not cover VNS for treatment resistent depression. Under the guise of science and despite an overwhelming positive response from physicians and the community, we will be taking another step toward stratifying health care for the rich vs. for everyone else.

Your approach is perhaps best clarified by an actual journal article (Smith,GC & Pell, JP. BMJ. 2003 Dec 20;327(7429):1459-61.)Department of Obstetrics and Gynaecology, Cambridge University, United Kingdom. gcss2@cam.ac.uk

Titled: Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomized controlled trials.

abstract as follows:
OBJECTIVES: To determine whether parachutes are effective in preventing major trauma related to gravitational challenge. Design Systematic review of randomised controlled trials.
DATA SOURCES: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists. STUDY
SELECTION: Studies showing the effects of using a parachute during free fall.
MAIN OUTCOME MEASURE: Death or major trauma, defined as an injury severity score > 15.
RESULTS: We were unable to identify any randomised controlled trials of parachute intervention.
CONCLUSIONS: As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute dgement should be left to experts, professional societies and experienced physicians, not to a thrid party payer technical group.Thank you for your consideration

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Vagus Nerve Stimulation for Treatment of Resistant Depression

Treatment options for treatment resistant depression must remain for Americans afflicted with this disorder. Most people who find themselves with TRD have already tried and failed numerous other medications and psychotherapies. Failure to cover VNS therapy for Americans with Medicare is an unfair discrimination against people who struggle with severe mental illnesses. VNS for TRD is an FDA approved therapy for TRD and as such should be covered by ALL insurance policies, including Medicare, as a medical treatment for a very disabling condition. The 1999 Surgeon General's report on Mental Health made it clear that mental health is FUNDAMENTAL to overall health and that we must break down the barriers to care for people with mental illness. It is unconscionable for the US government to discrimiate against its citizens with mental illnees by denying them access to an FDA approved treatment if they have the misfortune to have TRD.

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February 28, 2007

Attn: Beverly A. Lofton, MHA
CMS
7500 Security Boulevard
Baltimore, MD 21244

RE: NCA for Vagus Nerve Stimulation for Treatment Resistant Depression (TRD) (CAG-00313RC1-09-06

Dear Ms. Lofton:

I am writing on behalf of South Dakota Advocacy Services to comment on the National Proposed Decision Memorandum for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD).

South Dakota Advocacy Services is the designated Protection and Advocacy System for individuals with disabilities for the state of South Dakota. As a part of our work, we assist many individuals who suffer from depression. Based on our limited contacts with psychiatrists within our state on their knowledge of, experience with and use of the Vagus Nerve Stimulator, it appears to have proven to be efficacious when appropriately prescribed for individuals with Treatment Resistant Depression. In order to provide the broadest range of appropriate options to persons suffering from this debilitating disease, we request that the final national coverage decision include coverage of Vagus Nerve Stimulators to treat individuals with TRD.

If we may be of further assistance or if you have any questions or request any further information, please contact us at the number below.

Thank you for the opportunity to comment.

Sincerely,

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As executive director of the Epilepsy Foundation of Southeast Texas and the Epilepsy Foundation of Dallas/Fort Worth, covering 99 counties of eastern Texas, I have had the opportunity of working with many people who have benefited from the VNS for TRD.The Epilepsy Foundation, in collaboration the University of Texas Medical Branch - Galveston, conducts epilepsy medical clinics for 900 uninsured adults with seizure disorders. A large percentage of our patient population also experience TRD. It has been our observation that a number of VNS patients report that the treatment has significantly improved their quality of life.I encourage CMS to reconsider its position on VNS therapy for TRD.
Donna Stahlhut
Executive Director
Epilepsy Foundation of Southeast Texas
Epilepsy Foundation of Dallas/Fort Worth

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I have treated 8 patients with VNS for treatment resistant depression. Of the 8, 2 are now in remission 2 have had a response as defined by at least a 50% reduction in ham d scores. 2 of the other 4 patients have had some reduction in symptoms including a significant reduction in suicidal thoughts. Treatment resistant depression does exist, whether CMS acknowledges it or not. I've been practicing psychiatry for 12 years and I see it regularly. You can argue that treatment resistance is due to noncompliance or inadequate dosing of antidepressants but in the studies for VNS there was rigorous effort made to insure patients had failed adequate trials of antidepressants.

I am not surpised that private insurance companies have not found evidence to support VNS to be effective in treating depression. How many lawsuits do we see against insurance companies that fail to cover their approved treatments. They have little concern for patient welfare, only their profits.

CMS and medicare is once again discriminating against the mentally ill. Depression is a bilogical illness as real as cancer, cad,hypertension. There is a known bilogical basis to depression just as there is to heart disease. Stress makes it more likely someone will suffer an MI and those that suffer an MI and depression have poorer outcomes than those that don't suffer depression.It's interesting that these public comments for the NCD are not public as the first comments were. I guess it would be difficult to handle the public outrage that would be apparent over the web pages. I am discouraged but not surprised at your decision as the discrimation of the mentally ill continues. Hopefully, you will reverse your poor decision.

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I am a Neurology Nurse whose practice specializes in Epilepsy. During the course of using VNS Therapy in our intractable epilepsy patients we have noticed an obvious decrease in their co-morbid depression. Families have commented on the patients improved mood and alertness. We have implanted VNS Systems in two patients with depression after lengthy involvements with insurance companies. One patient who had been receiving quarterly ECT Treatments went more than a year without need for any ECT. This patient and her psychotherapist reported marked improvement in mood and quality of life. Recently a depressed patient awaiting insurance approval shared with us that medical costs for her ECT Treatments were over $100,000 in a single year. VNS, a minimally invasive procedure, not only has an obvious beneficial effect in co-morbid depression associated with epilepsy, but in my experience benefits patients with treatment resistant depression as well. Given the high yearly cost of maintaining remission with ECT it seems to me that VNS should prove to be a very cost effective treatment. Further more an improvement of depression in 17% of patients who have failed or are failing other modalities of treatment is substantial. My experience in managing over 80 patients with VNS systems implanted is that treatment is extremely well tolerated and serious complications very rare. I hope you will reconsider your decision and allow Medicare beneficiaries with mental illness (treatment- resistance depression) access to VNS Therapy which I believe will continue to prove to be highly effective in this patient group.

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I am a psychiatrist in private practice and have had one patient with treatment resistent depression who has undergone VNS placement. She had been receiving five medications plus electroconvulsive therapy every three weeks prior to VNS. She has shown sustained improvement since the VNS and no longer needs ECT and has been able to come off one of her five medications. She has not needed hospitalization and her symptoms of depression have improved and she is much more stable. The VNS therapy has exceeded my expectations, and I feel it should be an alternative for those patients who have treatment resistant depression. I might also add that I have no financial arrangement with Cyberonics.

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I work as a psychiatric nurse practitioner and frequently treat patients with treatment-resistant depression (TRD). For most of them, multiple antidepressant trials have failed them. Additionally, many have not responded to electroconvulsive therapy either. Unfortunately, suicide remains a very concerning risk for these patients. We have seen a great response in patients that were fortunate enough to have VNS. I hope that soon this treatment will be more available. It is, afterall, an FDA-approved treatment for TRD. I think over time this procedure would be more cost effective, especially considering the cost of multiple drug therapies and psychiatric hospitalizations. I ask that you please not deny this treatment for one of the most devastating psychiatric illnesses.

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I have extensive experience with treatment resistant major depressive disorder and bipolar depression through research and tertiary consultation work. Dr. John Zajecka and I are fortunate enough to be involved in the VNS Treatment Resistant Depression Registry which has given us the opportunity to follow approximately 30 VNS patients and treat about 19 of them. While most of them are early in the process we are beginning to see responses in some of these people at the three month mark and have seen remission after a year of therapy. The chance of a truly treatment resistant patient responding to VNS is greater than their chance of responding to the next drug that comes along. Their chance of maintaining response with VNS is greater than with medications. This is especially encouraging considering the number of people I have seen who may get an initial response from a drug but then loose that response.

Many of our patients have suffered from depression from many years. VNS is a potential long-term solution for these people who we know will be struggling with this disease for the rest of their lives. Third party payers will, in the long run, come out ahead because of the overall reduction in morbidity VNS can provide.

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As president of the Depression and Bipolar Support Alliance of Metropolitan Atlanta, I am personally familiar with the difficulties patients face as they attempt to find the best treatment options to help them achieve recovery. The many individuals who attend our mood disorder support groups each month deserve a full range of therapies. Many patients, unfortunately, experience treatment-resistant depression and can benefit from an option like VNS therapy. Patients should have access to any worthwhile, safe option that improves their chances of having a meaningful life again. I urge you to give VNS therapy every possible consideration to coverage for this FDA-approved option for Medicare beneficiaries.

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February 23, 2007

I am writing this letter because I understand that CMS has now published a request for public comment on the Draft National Coverage Policy proposing non-coverage of VNS therapy for treatment resistant depression.

As you are well aware, treatment resistant depression remains a major clinical problem and is strongly linked to suicide. Suicide remains the highest mortality rate for people aged 15 to 40 years old in the United States.

As a psychiatrist in clinical practice, I have often seen patients who have failed to respond to multiple combinations of medications, psychotherapy, and electro-convulsive therapy. They are at the edge of hopelessness and despair. These patients are high-utilizers, with frequent self-mutilation, suicide attempts, and need for inpatient hospitalization, not to mention repeated emergency room visits.

Since vagal nerve stimulation was approved by the FDA for treatment resistant depression, I have now had the opportunity to witness the improvement in five of my own patients who were lucky enough to have access to the treatment.

Of those patients, two have done spectacularly well, two have improved somewhat, and one has just begun therapy. In my small experience, it has been remarkable to see patients who had given up all hope, on the brink of despair, with constant suicidality, improve with this treatment.

Two of these patients were actually covered by Medicare.

On the other hand, I have patients who have been denied the procedure, who have failed to improve though provided with every conceivable modality of available treatment, including ECT. One such patient took a massive overdose of pills and ended up hospitalized because she had given up all hope that the insurance company would ever pay for the VNS therapy which she felt convinced would be helpful to her.

The STAR*D. (sequenced treatment alternatives to relieve depression) study illustrates that the remission rate in depression was only 28%. Patients who fail to achieve initial remission predictably have worse long-term outcomes. These patients with treatment resistant depressions often report severe hopelessness and suicidal ideation. As you are aware, data from the STAR*D indicate that after the fourth treatment, only about 7% to 14% of patients will remit.

If the concept of TRDEH (treatment resistant depression along with patients who have received or refused ECT, or have been hospitalized for treatment of depression) is adopted, one can quickly see that these are the patients who desperately need a treatment like vagal nerve stimulation. TRDEH patient; without it they tend to have annualized expenses of up to $40,000 a year.

In a study conducted by Burke WJ et al. (1) patients with treatment resistant depression experienced a reduction in hospitalizations and suicide attempts and ideation over a two-year period of treatment for VNS therapy. These data further substantiate reduction in utilization costs.

A study by Sackeim et al (2) confirmed that most participants who responded during the pilot and pivotal studies show durable clinical benefit, both at 12 and 24 months. For early responders, 63% and 72% showed substantial clinical benefit at 12 months, and these rates were 77% and 61% at 24 months. 79% and 65% of late responders showed substantial clinical benefit at 24 months. The degree of treatment resistance, and the delayed onset of response are two exceptional aspects of their findings.

In summary, the safety of VNS therapy is well established (more than 40,000 patients have received the treatment since FDA approval for epilepsy in 1997).

VNS continues to produce significant and sustained improvements after one and two years of treatment. And VNS therapy is the only FDA approved treatment for treatment resistant depression.

It may be our last hope for TRDEH patients. More significantly, VNS has the potential to produce significant reductions in health care utilization and health care expenditures in patients with TRDEH. Finally, I would reiterate that I find it very disturbing that Medicare covers the treatment of pharmaco-resistant epilepsy, while continuing to deny the treatment of pharmaco-resistant depression. I see this as one more bias against our mentally ill population who often do not have the ability to lobby for themselves.

It is our ethical, moral, and legal duty to supply this very important FDA-approved treatment for our critically ill treatment resistant patients. Thank you for inviting and reviewing these comments.

Sincerely,

Dinshah D. Gagrat, M.D.

References:

1 Burke WJ and Moreno FA. Suicidality and treatment resistant depression: Results from a 24 Month Trial of Vagus Nerve Stimulation (Poster) presented at the 156th American Psychiatric Association annual meeting in May 20-25, 2006 Toronto Canada

2 Sackeim HA et al, Durability of Antidepressant Response to Vagus Nerve Stimulation, International Journal of Neuropsychopharmacology October 2006

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I am a psychiatrist and I treat many patients with depression. Within that group there is a small subset of the severely depressed who do not repsond to conventional treatments. These patients use a tremendous mount of resources with multiple expensive medications, weekly therapy, disability (Social Security and private), ER visits and hospitalizations all with the main benefit for them being avoidance of suicide not wellness. I have 8 patients who I referred for VNS due to the failure of other treatments. One received it with benefits. They are desperate and are going through the motions in their lives trying to find hope. I implore you to reconsider your stance on payment for this novel treatment for those people who are suffering and deserve all available FDA approved treatments. Medicare has the opportuntiy to set an example of humane and cost effective care to other insurers. I believe VNS will help many people with minimal risk and will help reduce the long term cost of care for these patients. The small subset whose lives are destroyed by severe and disbaling depresison need this chance at life.

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CMS

Dear Sir/Madam:

I was distressed by the recent CMS ruling on funding for Vegus Nerve Stimulation. This decision that Vegus Nerve Stimulation should not be covered is truly short-sighted and seems to trivialize important health issues. I was particularly concerned by several assertions in this preliminary ruling. First, the suggestion that treatment resistant depression is not a well-defined concept, nor a problem, is frankly fallacious. As an NIH-funded investigator, and also an investigator who has participated in a number of different studies investigating both the ideology and phenomenology of treatment resistant depression, I take exception to the contention that this serious and potentially lethal medical disorder is being dismissed by CMS. At this time, approximately one-third of individuals who suffer from major depressive disorder are not responsive to initial and even first and second heroic attempts at appropriate and combinations of pharmacotherapy and psychotherapy. Unfortunately, even when there is an initial response, data from studies such as the recent paper in Neuropsychopharmacology, suggests that the response may be evanescent to pharmacotherapy (Rapaport et al, 2006, Neuropsychopharmacology). What is important about Vegus Nerve Stimulation therapy is the fact that a significant number of individuals with very chronic treatment resistant depression do respond within one year of implantation of the device. Furthermore, what is impressive is that approximately 70% of individuals who have had a Vegus Nerve Stimulator implanted will have a sustained response at the two-year evaluation point. This is better than any known augmentation therapy for treatment resistant depression at this time.

Treatment resistant depression is associated with unfortunately significant mortality from suicide. It also is associated with significant morbidity from co-occurring medical disorders as well as increased health care costs because of the depression resistant to standard treatment. A second aspect of the hidden costs of treatment resistant depression is the effect that it has on the family and friends of an individual. Treatment resistant depression has a devastating, long-term effect on relationships. Family and friends must spend a significant amount of time caring for such individuals and, unfortunately, it may lead to either the end of those relationships for the family and friends or significant diminution in the quality of life of family and friends who are loyal and able to support somebody with treatment resistant depression.

Therefore, in closing, I would suggest that for ethical, humanitarian, and scientific reasons it would make sense for CMS to reverse its stance and allow funding for Vegus Nerve Stimulation implantation and reasonable follow-up visits.

At this time, I have referred at least six patients for VNS through various insurance companies with no success. All of these patients have treatment resistant depression or severe mood disorder. I strongly believe all would benefit from this mode of treatment as they continue to suffer on a daily basis.

Sincerely yours,

Jill R. Zweig, D.O.

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VNS is a safe and necessary treatment in patients who do not respond adequately to the most agressive trials of anti-depressant medication. I currently have over a dozen patients, most of whom have been treated with VNS because they have Medicare insurance. The majority of these patients are improved with the treatment and approximatley 50% are dramatically improved. It is routine that private insurance companies refuse to cover VNS treatment for appropriate patients as "experimental." The unreasonable refusal of VNS treatment in "private insurance" patients causes prolonged suffering, increased loss of work and family trauma, and increases the risk of suicide. Private insurance companies should be compelled to cover VNS treatment in patients who meet criteria and who have been fully evaluated by a psychiatrist. Inclusion of VNS as a covered benefit will ultimately lead to lower overall health care cost, decreased patient suffering, and decreased risk of suicide. I speak from experience. I have seen that this treatment works. Please act swiftly.
Thank you.
David T. Holmes
Board Certified Psychiatrist

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I am a psychiatrist and have two patients that have opted for VNS therapy. The improvement of seve depression in approximately 30% of recipients may seem low to someone who is inexperienced, however, to the person who has struggled for years with this, it is well worth the effort. Would you ask someone with cancer not to opt for a treatment that offered a potential of 30% survival when all other options were exhausted. Deciding that people with epilepsy deserve this treatment and those with depression do not is not right.My patient who have received both consider it to have been helpful and one recently told me she would have been dead without it.

Please do the right thing in your decision to approve payment for this medical treatment.

jackie Neel, D.O.

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I am a registered nurse with a certification in case management. I am an employee of Cyberonics and I work directly with individuals that are seeking the help that you, CMS, are refusing. These are people that see themselves as misunderstood, as less of a person, as a person without any real hope of ever feeling connected to the world or to those around them. Some are able to hang on to a glimmer of hope; a hope that SOMETHING out there in the MEDICAL community will help them. Depression is a physiologic condition and it should be given the same importance as any other disease process. You are withholding a treatment that is their God given right to have…the pursuit of joy and happiness. Though I know we are working with a population of depression patients that nothing has helped them long term, that most have been suffering for 10-40 years. I also now from personal experience that VNS Therapy does provide them a better chance for recovery then anything else available to them; even remission is possible. I know this because of the personal accounts told to me by the individuals that have called telling me about how they have a new life after VNS Therapy. Their struggle now is to learn to live WITHOUT depression. Everything else has always failed them; its’ the expectation for them now. One has told me that in the early stages of the therapy, she noticed that the number and severity of the depressive episodes had decreased. She’s begun to think about the possibility of getting off Medicare disability and returning to the professional life which once gave her pride and fulfillment. She vehemently hates being on disability. I think about the man who once was a complete shut-in. He, also on Medicare disability, could no longer work, lost his marriage and all contact with the outside world. His only contact was his son, his therapist and psychiatrist. Now after VNS Therapy, he not only reports that he is responding, but has joined a gym and a dating service. As a human, as a person that has suffered from a depressive episodes in my life, I am empathetic to the pain they feel EVERY DAY; suffering from a overwhelming feeling of being trapped, of devastation, sadness, turmoil, and loneliness. How can you deny the only hope that they have? Not only should you think about the estimated 55,000 lives that are lost each year to suicide, but also how this affects the spouses, children, and extended family that suffer along with the depression patient. Living with a family member that has depression is difficult. Life after one you love has committed suicide is difficult and life long. These are things that stay with you your whole life and it feeds into the next generation. What about all those on Medicare disability because they are unable to support themselves or their family? What about all the lost productivity in the work force? Don’t you think the cost of depression is far greater? There is an emotional and financial cost that is never ending.

PLEASE give them a choice for improvement; to LIVE. Reverse you draft. Approve coverage for VNS Therapy. There are plenty of VNS Therapy patients that can tell you themselves of their response; contact them. Hear their storey for your self. At the very least, approve it with stipulations. Approve it for those that have attempted to take their own life, for those with depression that has needed in patient hospital management, for those that have made the difficult choice to try ECT, or for those that refuse ECT for their own personal or physical reason. I know that VNS Therapy works. I hear of its’ miracles every day. We (the patients I serve and I) are devastated by your proposal to deny coverage and talk of suicide has risen its’ ugly head because of your draft. You are making them wait too long and taking away their hope. Please talk to VNS Therapy patients. Do the right thing for your fellow man. Be a part of providing that miracle. And VNS Therapy is a miracle because for these patients, nothing else you have to offer them has ever worked. Vanessa Garrison, BSN, RN, FAACM

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February 25, 2007

To whom it may concern,

The purpose of this letter is to ensure that you recognize the Nebraska Psychiatric Society (NPS) endorsement of Vagus Nerve Stimulation (VNS) therapy for treatment of refractory depression (TRD) and, therefore, urge that you reconsider your elimination of coverage of this important treatment option.

The NPS (like our national affiliate the American Psychiatric Association) insist that VNS therapy for TRD should have parity coverage with VNS therapy for refractory epilepsy. The NPS presently attribute your denial of coverage to an error due to your unfamiliarity with the most recent scientific and economic data.

Peer-reviewed published studies show that VNS for TRD:

I am greatly concerned over the non-coverage draft decision issued on February 5, 2007 denying coverage of Vagus Nerve Stimulator therapy for patients with treatment refractory depression. As a psychiatrist and president of one of the largest behavioral health practices in the midwest, I am acutely aware of the percentage of patients who do not have an adquate response to traditional treatments for chronic, severe depression.

This FDA-approved treatment has been demonstrated to be helpful to a number of patients. There are a variety of articles supporting the utility of VNS therapy (please see below for a list of articles from the peer-reviewed literature).

While I am aware of the costs of this treatment and certainly would agree that one of the responsibilities of a physician is to be a good steward of the nation's healthcare dollars, it is unethical to deny the limited number of patients appropriate for VNS therapy access to this treatment option based on cost. After all, we do not do this when it comes to surgical procedures, cancer treatment, etc.

I have seen patients under my care and patients under the care of my colleages who have benefitted from VNS therapy when all other forms of treatment had failed.

I ask that you give careful consideration to reversing the decision to deny coverage for this form of treatment as it represents an important clinical tool in effectively treating this limited number of patients.

1: Sackeim HA, Brannan SK, John Rush A, George MS, Marangell LB, Allen J. Durability of antidepressant response to vagus nerve stimulation (VNSTM).Int J Neuropsychopharmacol. 2007 Feb 9;:1-10 [Epub ahead of print] PMID: 17288644 [PubMed - as supplied by publisher]

2: George MS, Nahas Z, Borckardt JJ, Anderson B, Burns C, Kose S, Short EB. Vagus nerve stimulation for the treatment of depression and otherneuropsychiatric disorders.Expert Rev Neurother. 2007 Jan;7(1):63-74. Review. PMID: 17187498 [PubMed - indexed for MEDLINE]

3: Isenberg KE, Zorumski CF. Treatment choices when options appear plentiful.J ECT. 2006 Dec;22(4):233-4. No abstract available. PMID: 17143150 [PubMed - indexed for MEDLINE]

4: Nahas Z, Burns C, Foust MJ, Short B, Herbsman T, George MS. Vagus nerve stimulation (VNS) for depression: what do we know now and whatshould be done next?Curr Psychiatry Rep. 2006 Dec;8(6):445-51. Review. PMID: 17094924 [PubMed - indexed for MEDLINE]

5: Borckardt JJ, Anderson B, Andrew Kozel F, Nahas Z, Richard Smith A, JacksonThomas K, Kose S, George MS. Acute and long-term VNS effects on pain perception in a case oftreatment-resistant depression.Neurocase. 2006 Aug;12(4):216-20. PMID: 17000590 [PubMed - indexed for MEDLINE]

6: Howland RH. Vagus nerve stimulation for depression and other neuropsychiatric disorders.J Psychosoc Nurs Ment Health Serv. 2006 Sep;44(9):11-4. Review. No abstractavailable. PMID: 16989326 [PubMed - indexed for MEDLINE]

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I am a practicing psychiatrist in Bloomington,ILand I have three patients right now on VNS for TRD. All of them are showing response within the time frame expected. All of them have tolerated this treatment and are very satisfied with rheir progress. I have several more patients awaiting approval for VNS. I support its inclusion as an option for TRD patients whose lives are chronically dampened by the debilitating effects of depression. I believe that it would be a disservice to deny these patients who may benefit from this treatment when nothing else works.

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I'm not sure who makes the final decision, but I really really hope you decide to let insurance cover vagus nerve stimulation for those people who suffer from treatment resistant depression. When someone is so depressed and they can't function they end up having to take time off of work and usually end up being hospitalized numerous times. VNS is too expensive for someone to just be able to pay for it out of pocket. I beleive, in the long run, money would be saved if insurance covered this treatment because those people who haven't been able to be helped by meds or ECT would have another option besides long term hospitalization.

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I was distressed to hear of the non-coverage decision by CMS for VNS for depression. I have a referral based psychiatric practice doing predominantly Electro-Convulsive Therapy. Thus, I see the most treatment resistant depression. I have 4 patients who have failed ECT treatments that subsequently had VNS implantation. Two of these 4 patients have had significantly positive responses. One woman had recurrent psychotic mixed mania whenever the interval between her maintenance ECT treatments was extended beyond once per week. On three occasions, she required re-hospitalization due to return of psychosis when we attempted to extend the interval between ECT treatments to just two weeks. We then needed to re-initate acute courses if involuntary ECT. Since VNS implantation, she has had no hospitalizations and no relapses over the past year, and we have been able to extend her ECT interval to once per month. I am convinced that the VNS device is responsible for this improvement. My second patient had terrible intractible depression, unresponsive to 30 ECT treatments. She was persistently and intensely suicidal. It is now 6 months since her implantation. She is at home with her husband, able to help around the home and enjoy simple pleasures. She is no longer suicidal. Though her depression is not completely resolved, she is significantly improved. Again, given the duration and severity of her depression, and her failure of ECT, I am quite convinced that VNS is responsible for her improvement.

A 50% response rate in my admittedly very small series of patients if very meaningful given the fact these patients had run out of all available options. It would be a tragedy if I could not offer VNS to my patients in the future.

Sincerely yours,
Theodore A. Goodman MD
Director Interventional Psychiatry
Sutter Center for Psychiatry
Sacramento, California

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As a practicing psychiatrist who cares for individual with severely ill, treatment refractory illnesses I strongly urge you to approve funding for Vagus Nerve Stimulation for Treatment of Resistant Depression (TRD). This treatment represents the last, best hope for a number of individuals with TRD, including individuals in my own practice. I have patients with refractory depression who have been through every other treatment without improvement and truly need the option of VNS. One of my patients was unable to hang on any longer to the prospect of VNS treatment and took his life. As a professor of psychiartry, I have a great interest in assuring that treatments are scientifically sound. I have reviewed the published evidence for VNS in TRD. While there is a modest response rate and modest effect size, treatment is likely to be lifesaving. If even a third of my TRD patients improved, and even if that improvement were partial, the benefit would be striking, given the suffering and disability that accompany TRD, and suicides might well be prevented. The costs of VNS are not great compared to the benefits. This is a treatment that needs to be made available now.

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February 23, 2007

RE: Vagus Nerve Stimulation

To Whom It May Concern:

Please be advised that I am the attending psychiatrist and Medical Director of the Rochester Center for Behavioral Medicine. I am aware that Medicare is now undergoing an assessment of the efficacy of Vagus Nerve Stimulation.

I currently have thirteen patients on this treatment. Several have been done within the last month or so. The remaining patients have had the placement in for at least six months. I am happy to report the patients are doing quite well and are tolerating the procedure nicely.

Treatment–resistant depression is a significant problem in psychiatry. Vegus Nerve Stimulation clearly plays a role in a portion of these patients. Many federally funded studies, including the recent Star D Study, shows that current treatments are of limited benefit.

I hope Medicare looks at this favorably and does extend payment for this most important vital therapy.

Sincerely,

Joel L. Young, MD

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VNS has proven through clinical trials to work. There are case history of people treated with VNS who have been able to go back to work and get off of Social Security Disablity. For years my husband and I have paid into Social Security. Individuals should not be denied the medical care they need. There are many Americans who suffer from depression. The cost in Economic money has been great. Vns therapy has improved the quality of life for many people. Many people who suffer from TRD are raising children. It is not only the sick person who suffers but the whole family. Living with depressed parents affect the develpment of children. The government spends millions of dollars on cancer research and other diseases, but the area of mental health is very low on the totem pole. It is an injustice to deny people the care they need. Very little was done for mentally handicapped until President Kennedy had a sister suffering from Downs syndrome then it became a priority to do something. It should not take something like that for the treatment of Treatment Resist Depression to recieve the medical care they need. Especially since the FDA has approve the treatment with VNS for individuals suffering from depression.

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Dear Sir/Madam:

I was distressed by the recent CMS ruling on funding for Vegus Nerve Stimulation. This decision that Vegus Nerve Stimulation should not be covered is truly short-sighted and seems to trivialize important health issues. I was particularly concerned by several assertions in this preliminary ruling. First, the suggestion that treatment resistant depression is not a well-defined concept, nor a problem, is frankly fallacious. As an NIH-funded investigator, and also an investigator who has participated in a number of different studies investigating both the ideology and phenomenology of treatment resistant depression, I take exception to the contention that this serious and potentially lethal medical disorder is being dismissed by CMS. At this time, approximately one-third of individuals who suffer from major depressive disorder are not responsive to initial and even first and second heroic attempts at appropriate and combinations of pharmacotherapy and psychotherapy. Unfortunately, even when there is an initial response, data from studies such as my recent paper in Neuropsychopharmacology, suggests that the response may be evanescent to pharmacotherapy (Rapaport et al, 2006, Neuropsychopharmacology). What is important about Vegus Nerve Stimulation therapy is the fact that a significant number of individuals with very chronic treatment resistant depression do respond within one year of implantation of the device. Furthermore, what is impressive is that approximately 70% of individuals who have had a Vegus Nerve Stimulator implanted will have a sustained response at the two-year evaluation point. This is better than any known augmentation therapy for treatment resistant depression at this time.

Treatment resistant depression is associated with unfortunately significant mortality from suicide. It also is associated with significant morbidity from co-occurring medical disorders as well as increased health care costs because of the depression resistant to standard treatment. A second aspect of the hidden costs of treatment resistant depression is the effect that it has on the family and friends of an individual. Treatment resistant depression has a devastating, long-term effect on relationships. Family and friends must spend a significant amount of time caring for such individuals and, unfortunately, it may lead to either the end of those relationships for the family and friends or significant diminution in the quality of life of family and friends who are loyal and able to support somebody with treatment resistant depression.

Therefore, in closing, I would suggest that for ethical, humanitarian, and scientific reasons it would make sense for CMS to reverse its stance and allow funding for Vegus Nerve Stimulation implantation and reasonable follow-up visits.

Sincerely yours, Mark Hyman Rapaport, M.D., Chairman,
Department of Psychiatry and Behavioral Neurosciences
The Polier Endowed Chair in Schizophrenia
and Related Disorders
Cedars-Sinai Medical Center
Vice Chairman and Professor in Residence
Department of Psychiatry and Biobehavioral
Sciences
David Geffen School of Medicine at UCLA
8730 Alden Drive, Thalians, C-301
Los Angeles, Ca. 90048

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I am a psychiatrist who was involved in the D-02 trial that was done for FDA approval, so I have a lot of experience with using the device and have a sense of which patients may benefit.Since FDA approval our center has implanted about 12 of the devices in carefully selected patients (but only after a real battle with their insurance carriers). The the majority of these patients have been robust responders to the intervention and they are very happy with the device; in several cases they say it has been life-saving. One of our very treatment resistant patients who was an early responder has actually formed a support group for other VNS patient responders. My positive results are obviously a small sample; therefore it is important to continue with the post-approval studies being conducted by Cyberonics. I should mention that I have no financial incentive to currently promote the device; I am a salaried University Professor who does not realize immediate financial gain from recommending implantation of the VNS; I am only trying to offer reasonable therapies to depressed individuals.

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I am a Psychologist who works with many clients with TRD. I am shocked that Medicare would even consider denying coverage for this procedure. The clients I see have been through many, many treatments for depression, and have often been unable to hold jobs, maintain families, and have been on disability for lengthy periods of time. Even if VNS works for only a fraction of them, the savings in services alone will make up the cost of the procedure within a few years, to say nothing of the improvement in the quality of life for these folks. I urge you to pay for VNS, both as a provider of mental health services and as a tax payer.

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I am a psychiatrist practicing in an academic setting in which 80% of the individuals whom I treat have a chronic mood disorder. As a clinician-administrator I also understand issues of cost containment and appropriate utilization of evidence-based treatment modalities. Non-coverage of VNS as is being proposed by CMS would be a terrible mistake and would take away a potentially useful treatment modality for a group of individuals who already suffer great loss, hopelessness and emotional suffering.I certainly advocate judicious screening as to the appropriateness of an individual for this treatment but to deny access to VNS entirely would really seem to be unjustified.

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I hope that VNS will be available to all physicians and clients that desire to use it for treatment resistant depression. The decision to go foward with VNS should be between the doctor and the educated patient as long as safety has been proven. Successful treatment with VNS would reduce the cost of treatment for medicare and medicaid by keep patients out of the hospitals and emergency rooms. VNS for some patients would simplify their treatment,possibly reduce or get rid of medications,and if succesful return them to a full life. Please let those, that so far have been unable to beat depression, have another opportunity for happiness.

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CMS
Att: Beverly Lofton, MHA
Ref: NCA for VNS for TRD (CAG-00313R) C1-09-06
7500 Security BLVD
Baltimore, MD 21244

Dear CMS Officials:

I was disappointed to read the CMS decision regarding covering VNS for patients with treatment resistant depression (TRD). I am sympathetic to the notion that health care costs are rising and are not infinite, and we must be careful in choosing what we pay for out of our total health care budget. I can also understand that coverage decisions should reflect both the scientific data behind whether a treatment works, and also whether it is cost-effective. A reasonable person could decide that the current body of scientific evidence concerning VNS as an antidepressant is insufficient at this point to justify coverage. I agree that more randomized controlled clinical data concerning safety and efficacy would inform the field and hopefully settle the debate. From a science standpoint, we do not have Class I evidence of efficacy, and some might reasonably decide that full funding should await more data.

I am writing however to comment on an incorrect aspect of the overall report that is somewhat alarming to me as a psychiatrist and clinical researcher specializing in finding new therapies for depression.

Depression is still not well understood by many in our society, and still has some associated stigma. There was an alarming lack of understanding of the illness in the report, as well as some disconcerting statements regarding depression that might stem from biases in those drafting the report. I will quote from the report and then explain the problem.

“The concept of treatment resistant depression is vaguely defined, subject to varying determination, and until a scientifically valid definition exists is of little help in treatment selection for individual patients.”

This is patently wrong. As a young researcher in the early 1990’s I was amazed that the field of depression had the wrong notion that all patients responded to front-line medications, and that episodes typically lasted only 6 months and then remitted. I was working however in the NIH intramural program where we were constantly flooded with patient requests from around the country. These patients had chronic depressions that did not respond to medications or even ECT. Uniformly all depression experts now know that TRD exists (perhaps 20% of cases of depression go on to TRD), and that we do not have adequate treatments for these patients. We also know that they have a real illness, and are not suffering from a personality disorder, or ‘wanting’ to be ill, as some have speculated in the past. Whoever wrote the above statement needs to read the newly released STAR-D results showing that TRD exists, and that we need to approach the treatment of these patients in a different and more aggressive way. Current treatments do not work. It is true that there are different definitions of treatment resistance. But that is understandable in that treatment resistance exists on a continuum, much like staging for cancer. One can have various definitions depending on where you want to focus a treatment. The ATHF used in the VNS studies is the most widely used measure of TRD and is the current standard. It is logically wrong to state that we cannot and should not do studies in this population until we have a standard definition.

Thank you for allowing me to comment. You have a most difficult task in determining how health care dollars should be spent. It is most important that you first and foremost understand the diseases that cause people to seek treatment. Your group appears to need some education about depression, especially when it becomes treatment resistant, which is so common and has so much associated morbidity and mortality. We must find cost-effective treatments for these patients, and then pay for it so that they can return to functioning.

Sincerely,

Mark S. George, MD
Distinguished Professor of Psychiatry, Radiology
and Neurology
Director, Center for Advanced Imaging Research (CAIR)
Director, Brain Stimulation Laboratory (BSL)
Medical University of South Carolina

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The refusal of medicare and certain other insurance companies to pay for needed treatment for TRD is unconcsionable, especially when the need is well documented and the patient meets criteria for TRD as defined by the Food and Drug Administration (FDA).

People with TRD are a small subset of those with depressive disorders, and generally use many expensive medications often in combination, have failed trials of ECT, have used many expensive days in psychiatric units (sometimes often also monitored beds in intensive care units following unsuccessful suicide attempts), and are unable to work or have productive relationships. People affected by TRD are at chronic risk for suicide. Are people having physical illness with high risk of fatality similarly denied available and needed treatments? I am currently treating 8 people with TRD who have VNS. The improvement is better than expected, especially over time and when the family observations are included. It is also helpful to ask each patient to keep a journal starting before VNS dosing and thereafter. It is surprising even to them how much function they regain after dosing, even while they may still feel depressed mood. "Leaden paralysis" and hypersomnolence virtually disappear. One person was able to complete her studies to become a minister and complete ordination. This was only a dream previously due to TRD. Another has been able to resume coaching basketball. Another has been able to stay out of his recliner during the day and take a walk each day. He speaks for the first time in years about getting a job. These are only a few of the positive results of VNS. The refusal of insurance companies to pay for VSN for appropriate people with TRD is very short sighted financially, shows disregard for the laws regarding parity, and should not be allowed.

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Vagal Nerve Stimulation for severe treatment resistant depression will not be widely used, but it is an important, life-saving, intervention that must be available. While I have an extremely busy practice, I have only one patient on VNSand it has proved the only effective treatment in over 20 years of various medication trials and extensive psychotherapy. It has afforded my patient more benefit than literally hundreds of medication combinations. I strongly urge its coverage by Medicare and other third party payers. For too long, psychiatric conditions have received only lip service from insurers. The long term economic benefits from VNS in terms of decreased morbidity and decreased healthcare costs clearly justify its inclusion into covered services.

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As a board-certified psychiatrist, I treat many patients that continue to suffer and absolutely doo not respond to any of the currently available medicare-approved treatments. The patients that I have treated with VNS have uniformly done well and several have used the term "miracle" and "Godsend" to describe their response.It would be a tragedy to deny this safe,efficacious and well-researched treatment option to patients with life threating illness.I strongly encourage CMS to work with physicians to continue the long-term study with VNS already being reported in the literature.

Sincerely,
Joel Holiner,M.D.

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We have a patient that was implanted with a vagal nerve stimulator in August 2006. She has a diagnosis of major depression. She is very excited that she is able to do things that she has not done for years. She says she is very thankful for having the oppertunity to have the vns implanted. This patient was so excited she wanted to share with others about her success so she called a local tv station and they did a segmaent on the news with her. We have gotten many calls from people inquiring about the vns for depression. It is too bad these people get a little glimer of hope but have to be told we cannot do the surgery due to insurance guidelines.

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I am a psychiatrist in Fort Worth Texas who has had 3 patients receive vagal nerve stimulators. All three are functioning quite well and have been able to decrease their dosages and numbers of medications. None of the 3 have required hospitalizations since receiving the stimulators and all three have tolerated them well. This is not a treatment for the majority of patients. The FDA indication spells out the need for chronicity of illness and documented treatment failures. Denying access to the patients who need it and by definition are the most ill seems unsupportable to me. It has been proven effective and safe and is a life-saver to many patients. Please don't deny them a useful treatment option.

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Please make sure that Vagus Nerve Stimulation is approved for payment by Medicare. This is an FDA approved treatment for depression. We have had 20 patients who have had tremendous results.

How can you justify pacemakers for the heart, and deny patients with depression the relief they desire? Depression can be very life threatening.Please allow these patients the opportunity to be functioning in society at the level they desire and deserve. Please approve VNS for depression so that we can move these patients off the disability rolls and back into the workforce where they need to be!

Thank you for your consideration.

Rhonda Bearden

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I am disappointed that CMS did not agree to reccomend VNS for medicare coverage. We have seen a number of patients with severe treatment resistant depression whose insurance did not agree to allow VNS treatment. The draft cites the variable nature of symptoms in depression (both mild and severe) that make the data from VNS difficult to believe. Even the DSM iterations note that depressed mood is "most of the time" which denotes some variablity. I think this is a total distortion of psychiatric research. The assessments take that variability into account. We have followed VNS patients during the phase 3 trials that were done at the MUSC under Dr. Mark George and can attest to the improvement these patients experienced. I recognize the results of the research are modest but clearly clinically significant. A 30% improvement is impressive for such individuals. Treatment resistant depression is common and poorly understood. Any treatment that would modify this painful and potentially lethal condition would be a great benefit to patients and their families. I hope CMS reconsiders their conclusions.

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Greetings:

My name is Dr. Mark Woyshville; I am a psychiatrist with a number of treatment-resistant depressives in my practice. To date, I have three TRD patients implanted with the VNS device. Two have been titrated into the realm of therapeutic efficacy and are doing well; the next step is to begin to streamline their complex, polypharmacologic regimen to lower the burden of risk associated with same. The third patient is early in titration, during which time ensuring tolerability is the immediate goal - and indeed, he is tolerating the VNS very well, and anxious to continue titration.

In addition to my personal experience seeing three patients through from contemplating the device to dealing with insurers to getting them implanted and titrated, I also attend our local VNS for TRD support group, which meets monthly at a nearby hospital. There, I am able to witness the longitudinal progress of many patients (7 to 10 at any given time) who have been implanted; 100% OF THESE PATIENTS ARE DISCERNIBLY IMPROVED, some remarkably so.

I am grateful for the opportunity to submit a public comment in support of this remarkable treatment modality offering hope to patients with severe, refractory depression. In addition to their personal suffering, their condition is costly in terms of time, talent, and lost human potential. Finally, I might add that it is only a matter of time before the literature catches up to what we physicians "in the trenches" are experiencing treating TRD with VNS. Thank you for your consideration.

Cordially, Mark J. Woyshville M.D.

PS: I am emailing my CV as an attachment to CAGinquiries@cms.hhs.gov

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I am a board-certified psychiatrist in clinical practice for over 20 years. I have a substantial experience with treatment-resistant depression. Often, I am left with very little choice of treatment when none of the currently available treatments, including ECTs, are effective in bringing about an acceptable improvement in the patient's condition.

Since VNS became available, I have had one such patient implanted and over the next several months, he has shown improvement in his depressive symptoms with no suicidality anymore (before the implant, it was a daily struggle fighting that impulse to stay alive). He is also functioning better with minimal medication burden. A second patient, a young married female with many years' history and under heavy burden of medications with little improvement, was just implanted 2 weeks ago, and we are hoping to see a response in the next few months.

The point is, that for such patients, there are no reasonable alternatives, and VNS offers one such alternative. The studies conducted of VNS efficacy, choosing those patients that are typically excluded by drug studiesnamely, the difficult to imrpove depressed patientshave been promising, and personally, I can see how it can work in those patients. The scientific underpinnings of VNS are sound, and the near absence of any other unwanted effects (common to medications) is an understated advantage.

I strongly recommend that this treatment be approved for TRD and coverage for it made available widely.

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There is a young lady in Arab, Alabama who has suffered from depression for many years. She is constantly in and out of the hospital with this condition. She can't hold a job and the expense to her and her family are crippling. I believe she would be a number one candidate for this procedure. She really has nothing to lose and everything to gain from this. Medicare and Medicaid should really be in the business of helping to improve people's lives, not make them worse by denying coverage on something that could make a world of difference in not only this young lady's life, but many that suffer this horrible illness.

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Would consider the state of efficacy and effectiveness evidence for and against VNS for TRD,cost and risk of harm in matrix form, using similar standards and benchmarks as for otherwise treatment resistant epilepsy. This treatment has a very long delay prior to response, and true placebo controlled trials for 9-18 months are questionably ethical and would be very difficult to recruit for. For patients with the most severe, recurrent major depressive disorder WHO HAVE FAILED BILATERAL ECT with 8 (eight) or more sessions on separate days, or had medical contraindication for ECT, and failed specialty psychopharmacological treatment for depression with at least 10 antidepressants at full doses (unless not tolerated), including at least one trial of clomipramine, one trial of tranylcypramine, and combination of an antidepressant with T-3, lithium and atypical neuroleptic. VNS should be available as a probably effective treatment with a modest effect size for the small subgroup of patients who have truly severely resistant depression.

The odds of response for such a difficult to treat population compare favorably re cost, risk of harm and even level of evidence for patients with recurrence or rapidly progressive cancer after failure of standard chemotherapy regimens. The strength of evidence and lack of placebo controlled trials is similarly low in such populations. Only through long-term followup with very large treatment registries will there be adequate data to evaluate treatment outcomes in TRD cases, analogous to cancer (tumor) registries.

Specific suggestions to minimize the cost of open access to this last resort treatment:
1) Make access and Medicare, Medicaid coverage contingent on clear but complete request with copies of medical records sent to CMS as part of application for prior approval

2) Approve a limited number of regional centers of excellence with high volumes of ECT and treatment of patients with the most severe depressions. These centers are likely to be university medical centers

3) Require participation in outcome registry as condition of coverage this could be in deidentified manner using internet link filled out by MD; would need CPT code to cover additional burden of time if more than small dataset required. Could consider urging patients to complete interactive voice response or internet based deidentified database for outcome monitoring. Consider small fee for non-participant of registry monitoring to defray costs of monitoring; those participating would be paying with their time and trouble.

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VNS appears to be one of the most effective psychiatric treatments for depressive illness.

It is the only known treatment for depression that gets more effective with time. Robert Post MD, prior director of the Depression Division of the NIMH, has personally told me this is the most effective treatment we have in psychiatry.

Charles Conway at St. Louis University has had 40% remission with his research patients in Treatment Resistant Depression.

I have recommended VNS to several patients with treatment resistant depresssion who would benefit greatly if their insurers would approve the procedure. They would be required to serious consider providing this benefit if CMS developed criteria for approval.

Please help this population of unfortunate patients.

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Mental illness is a devastating disease that affects l in 5 families, NAMI Dallas advocates for people living with mental illness to have as many treatment options as possible to disucss with their doctor. Therefore, we urge you to approve Medicare coverage of VNS therapy so that people stricken by treatment resistent depression (TRD)may have this option to consider with their doctor. There are 1.3m people diagnosed with TRD; only 10,000 would ever qualify for the treatment. VNS is the only FDA- approved treatment for TRD. Over 2,500 already have the implants.

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The vagus nerve stimulator needs to be covered for people who have not responded to other treatments for depression. These patients are in and out of the hospital often and money could be saved if the VNS worked for them plus giving them some quality to their life. Depression is a brain disorder and Medicare does not limit treatment for chemotherapy even when there are not proven results. I'm a nurse and have seen many treatment options given to people and paid for by Medicare even when the chances are slim they will help. Please do not discriminate against people with brain disorders. This is a very debilitating illness and people need options when traditional treatment fails. Thank you for your consideration. Brenda Johnson

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I see a number of patients who suffer from severe disabling depressive symptoms over years despite multiple heroic medication and therapy combinations (including ECT therapy). I have one patient who has benefitted greatly from VNS therapy, and at least 5-6 others who would definitely have tried it except for lack of insurance coverage for the procedure. With my one patient, I have found it to be a well tolerated and easily used therapy, that I welcome into the armamentarium of treatments for severe depression. I was very dissappointed to learn of the negative decision and I sincerely hope that Medicare will rereview the decision and reverse it. Sincerely, David M. Holajter MD, Board Certified Psychiatry. 2/19/2006.

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Although I feel that VNS should clearly be limited to those patients whose prior treatment trials have been adequate and multiple (without adequate responses), it seems to me that there is a definite place for this therapy. I have, so far, been very impressed with the responses that I have achieved (albeit a limited number of cases). I have reviewed the published data in some detail and I feel that, in view of the limited overall response data for severe mood disorders, as well as the inability to access EST in many patients who are refractory, that this option needs to be available.

I have been practicing in the same community in AR for 38 years.

Max Baker, M.D.
Board Certified in Psychiatry

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I am a clinical professor of psychiatry at UCLA. I have well over 12,000 patients in my career. Thousands of them have "TRD". The NIMH STAR*D trials showed very low response rates to Parnate, Mirtazapine plus Venlafaxine in TRD patients. We have very few options to offer these patients. VNS is an option that works at least as well as these medicines performed in the NIMH trial. Please consider approving the use of VNS in Medicare patients.

Thank you for your consideration. Our patients need this treatment available to them.

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I am a psychiatrist in Oklahoma who treats Major Depression and other mood disorders. Treatment resistant depression is one of the biggest challenges I face because of its devastating effects for the individual involved with impairment in work performance, relationships and internal sense of well-being. People with TRD are at a much higher risk of suicide. The families of those who suffer TRD are also affected by the loss of their family member who never seems to return to a normal state again. Divorce and other psychiatric conditions secondary to the profound hopelessness of living with a person with TRD is common. Vagus Nerve Stimulation is a novel treatment approach with proven efficacy for TRD. The risks are small given the minor procedure involved. The benefits are potentially life-changing for the patient as well as their family. The issue of reimbursement for this procedure is critical to offer a patient, who, as a result of their TRD, is already in a financially compromised state. I implore you for the sake of the many people whose lives are at stake to change the position of reimbursement to make it a possibility for those in most need of HOPE.

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I would like to add my experience of over 1 year using VNS for treatment-refractory depression. I am a primary investigator for a Cyberonics funded study of VNS and have enrolled 12 patients thus far, some of whom are control subjects without implantation. 2-3 patients with implantation have already described noticeable improvement with their depression using VNS while none of the control group has changed. My patients have averaged over 10 drug/ECT failures prior to VNS, and even in this highly refractory group, they are deriving benefit. While my numbers are still low, other researchers are finding some similar results. We are limited in enrolling these patients because of insurance denials, fueled by the Medicare denials. I believe that these denials are causing additional risk of harm to individuals who would otherwise be candidates for VNS. It would seem appropriate to me for a guideline to be developed to provide clinicians with an option to use VNS in well selected patients, rather than simply rejecting all applicants, which is now starting to happen. One of my patients paid cash for his surgery, amounting to an expense of $20,000, even though he has limited funds. This demonstrates the desperation these patients experience. Now that the FDA has approved this treatment, limiting all access is further stigmatizing treatment and also further discriminating against these ill people. I urge reconsideration for well selected, appropriate candidates to receive VNS.

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I always think a case example is the most powerful tool I have to advocate for Vagus Nerve Stimulation (VNS).

I see a lot of Treatment Resistance Depression because I do a lot of Electro Convulsive Therapy (ECT) in Milwaukee, Wisconsin. I truly believe major depression is 90% treatable, yet I see the 10% that have not responded.

One of my patients, who was literally getting maintenance ECT on a monthly basis for years and having a good response as long as we continued ECT, finally received VNS. Since then she had a few more ECTs and now has not had an ECT treatment in over 8 months and she is feeling better than ever.

I don’t anticipate doing any more ECT treatments. I am clearly saving well over $18,000 a year by not having to do anymore ECT treatments. She is happier and for the next decade I’m convinced her VNS will save well over $150,000 in health care costs – not to mention the improved health and happiness of my patient.

I believe we need a system to identify the best patients for VNS. But, let’s not let this get in the way of a very effective treatment.

Sincerely,

Eric W. Kaplan, MD
Medical Director of In Patient Psychiatry
Columbia St. Mary’s Hospital
Milwaukee, WI

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We believe that people with TRD deserve benefit access to VNS Therapy. Denial of such access is truly a disservice to the health and well-being of those afflicted with TRD. As witness to those who suffer with TRD it is a heart-breaking and life-altering situation not only for those afflicted but for all those who love and care for them. VNS Therapy is often a last resort and at that an absolutely necessary treatment in making possible a hopeful future for those in need. Life without benefit access to the resource of VNS Therapy can proove to be not only debilitating, but-DEVASTATING.

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While I have no research data to support the efficacy of this procedure for TRD. FDA has found it to be appropriate for this condition. I find it incredable that several nonpsychiatric physicians and a lay person recommends coverage for this procedure not be include in the CMS. It is not recommended by psychiatrist unless all other treatment modalities have proved ineffective. Obviouslly these individuals havenot had contact with persons and their families who suffer daily with TRD. The human and economic loss is beyond comprehension not to mention the loss of life to suicide in TRD.

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I'm a psychiatrist with 3 severe treatment-resistant depressed patients with the VNS implanted. Two of them had ECT - one helped but relapsed and the second it didn't help at all. All 3 are improving, one already in remission after 6 weeks. One survived his house catching fire and dealing with the agony and frustration of remodeling and doing well. All 3 have been followed with Beck Depression Inventory depression scales, all 3 have steadily improved. Two of the 3 have been chronically and seriously suicidal and VNS has helped all three. All psychiatrists I've spoken with who have patients with VNS implanted have had positive reports on every patient. I want this procedure to remain viable and is far less expensive than hospitalization, repeated ECT and offers hope to the hopeless.
Lane M. Cook, M.D.
Board Certified Psychiatrist

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I am a board-certified psychiatrist practicing in the central Massachusetts area. I presently have two patients who have been implanted for at least six months, and four other patients in the early stages of implant. The two patients who have been implanted are showing remarkable improvement in mood. Both of these patients suffered years of severe depressive symptoms, and one has had several serious suicide attempts. The suicidal ideation has completely remitted over the last three months.

The response to the device has been consistent with the study data; one patient showed improvement after three months, the other began to show improvement six months after implant. I am greatly optimistic that the four patients who have just started treatment will respond given the response of my first two patients.

It is unfortunate that a device approved by the FDA is undergoing this level of scrutiny for its use in depression. It appears that achieving mental health parity in insurance reimbursement remains an ongoing struggle, despite all the state and federal legislation on the matter. Thank you in advance for your positive report on VNS for treatment resistant depression so that my patients will not continue to struggle with their illnesses while a potentially life-saving treatment dangles unreachably in front of them.

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FEBRUARY 15, 2007

TO WHOM THIS DOES CONCERN;

Attn: Beverly Lofton

Please make VNS treatment available for those most ill with chronic depression those most at risk for suicide.

Here is my EMPIRICAL evidence

1. You may consider a 30% remission rate as a result of VNS therapy to be low, but if VNS therapy were available to those most at risk for suicide, the 11th leading cause of death in the US (30,621 suicides in 2001 and 132,353 suicide attempts), suicide and suicide attempts would be drastically reduced. Many lives would be saved and hospitalizations unnecessary. (From the CDC Center for Disease Control.)http://www.cdc. gov/ncipc/ factsheets/ suifacts.htm Furthermore, according to the CDC (link above), the elderly 65 years and older the risk of suicide is much greater. These are the citizens that you are suppose to be advocates for.

2. If a medical device or treatment procedure were available for terminal (treatment resistant) cancer, heart disease, and other life-threatening illnesses, a 30% remission/recovery rate would be considered miraculous and embraced by the medical establishment as front-page news.

By denying this treatment to the sickest of the sick, each of you (decision makers) is personally responsible for the unnecessary suicide in the months and years to come. This small sub-set of people that suffer and do not recover from clinical depression are the most at risk for suicide and account for a very large number of those people in the suicide statistics.

That is my EMPIRICAL evidence. Your baselines are skewed in favor of physical diseases, and your prejudice against mental illness is blatant.

Thank you kindly for giving us a chance to live.

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When you reviewed the clinical trials of using VNS, the majority of the population that were studied were middle-aged women who are likely perimenopausal (or menopausal). None of the published studies investigated the role of hormone deficiency states (i.e. estradiol deficiency) in the treatment-resistant cases. Mid-life hormone imbalances or deficiency in 17-beta estradiol may be the real reason why there was a lack of response to antidepressants. There should be more studies evaluating the causes of treatment resistant depression BEFORE using VNS, particularly in middle-aged women (who are the "typical" patient). Also VNS will not work if the person is not eating regularly (with adequate essential amino acids) to synthesize the neurotransmitters (e.g., serotonin, norepinephrine, dopamine). Lack of nutrition that makes the neurotransmitters may be a potential reason why patients may not be responding to antidepressants. Antidepressants cannot work with the person making the neurotransmitters every day and this is directly related to their nutrition (i.e., intake of complete proteins), sleep (when neurotransmitters are synthesized during REM sleep), and exercise (when neurotransmitters are released). I would propose that "treatment resistant depression" may be related to poor nutrition, no exercise, minimal sleep, and hormonal imbalances that occur mid-life. Also many patients are left on benzodiazepines that should work against the efficacy of antidepressants and VNS. Until these are checked and evaluated, the use of VNS is really hopeless. You need to educated prescribers to think of the causes of treatment resistant depression before using polypharmacy or VNS.

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One of our patients was treated for intractable epilepsy, also suffering with depression. He had many ED visits, hospitalizations, office visits and on high dose meds. The VNS literally changed his life; seizure frequency was markedly reduced. His mood and cognition improved; be takes more interest in his personal hygiene, has developed new relationships including a girl friend, does better in school. ED visits are about 1/10th of his baseline. We don't see him in the hospital every month. The new neuro residents have not met him....all very positive changes since VNS. This was beyond our expectations, by far.

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Dear CMS,

As a practicing psychiatrist, I was greatly discouraged to hear of the proposed ruling regarding Medicare coverage for medical nerve stimulation.

I certainly have an appreciation for limited resources and financial outlays that we as a nation can provide. The proposed decision on this issue reflects a disturbing trend in the continued discrimination of equal accessibility to life-saving therapies of the severely mentally ill.

In light of the FDA approval of a glimmer of stimulation as a modality treatment for otherwise refractory patients appears to be in direct conflict with your rationale for not authorizing coverage of this procedure.

It is my recommendation, rather than exclude access entirely to a therapy that has been clinically observed to help some individuals as compared to placebo control groups as required by FDA, to take a more honest position regarding what the government and financially partition for the treatment of the mentally ill. This further my suggestion that if a higher threshold of evidence is required either clinically or economically for the benefit of this therapy, that such threshold be defined openly to both cyber Tronics as well as the public might wish to access this form of treatment if there were at least some level of support financially.

I have the benefit of having had a patient implanted for Vegus nerve stimulation and having had this service covered by Medicare.

This patient is now able to function without the pain of depression and frequent suicide attempts, and hospitalizations. Though this patient will require medical follow up for the remainder of her life, she is in fact having a life, and has reduced her consumption of medical resources including hopital stays and office visits.

It is my hope that you will strongly reconsider the proposed decision. In a the recent spirit of "no child left behind" one must wonder if that is really true if that child or their parent are mentally ill.

Sincerely,

Nicholas A. Zeltvay, DO

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I am a board certified surgeon who became involved with vagal nerve stimulator implantation for treatment resistant depression after discussions with some of my psychiatry colleagues.

Although I am not expert in the diagnosis and treatment of depression, I would like to comment on my experiences and observations as a medical professional in these patients follwoing placement of the vagal nerve stimulator. I have seen that these patients have improved clinically. Many of these patients are on multiple antidepressant medications. Following the VNS implantation, they have been able to reduce the numbers of medications required to control their depression. They anectdotally tell me that they "feel better" perhaps from less interaction of the previous multiple pharmacopia they were using. This result has been also observed by family members and the psychiatrists who have been following them for years with little previous improvement. There appears to be a reproducible benefit to these patients.In light of the fact that there appears to be improvement in these patients in ways that are notentirely quantifiable but are repeatedly reportedby the patients, family and their physicians, I urge CMS to continue funding the implantation of these devices into these unfortunate patients with resistant depression.

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I am a psychiatrist and program director for psychiatry at St. Elizabeth Hospital in Youngstown, Ohio. Treatment resistent depression is a real entity and costs the health care system thousands of dollars in recurrent hospitalizations, doctors visits, and medications. There is also the cost of lost productivity and social security benefits. Vagal Nerve Stimulation achieved approval from the FDA in treatment of depression, and should be covered by health care plans. It does result in significant costs, but treatment resistant depression results in approximatly the same amount of funds being expended, just in several different areas over a longer period of time. Beyond the issue of cost is the issue of ameliorating human suffering, and doctors need all the tools available.

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Please make this treatment available for those most ill with chronic depressionthose most at risk for suicide.

Here is my EMPERICAL evidence.

1. You may consider 30% remission as a result of VNS therapy to be low, but if VNS therapy were available to those most at risk for suicide, the 11th leading cause of death in the US30,621 suicides in 2001 and 132,353 suicide attempts, these numbers would be drastically reducedlives saved and hospitalizations unnecessary. (From the CDCCenter for Disease Control.http://www.cdc.gov/ncipc/factsheets/suifacts.htm Furthermore, according to the CDC (link above), the elderly65 years and olderthe risk of suicide is much greater. These are the citizens that you are suppose to be advocates for.

2. If a medical device or treatment procedure were available for terminal (treatment resistant) cancer, heart disease, and other life-threatening illnesses, a 30% remission/recovery would be considered miraculous and embraced by the medical establishment.

By denying this treatment to the sickest of the sick, each of you (decision makers) is personally responsible for the unnecessary suicide in the months and years to come. This small sub-set of people that suffer and do not recover from clinical depression are the most at risk for suicide and account for a very large number of those people in the suicide statistics.

That is my EMPERICAL evidence. Your baselines are skewed in favor of physical diseases, and your prejudice against mental illness is blatant.

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I am a doctoral psychologist and work with many serious and persistently depressed, treatment resistant depressed clients. For those that has tried everything, including ECT and have decades of struggle with daily suicidal ideation, this VNS treatment is needed to save lives. I urge you to approve the use of it in these severe cases. Mental illness needs to have the same credence as other illness for treatment. Many mentally ill people have suffered from lack of good coverage from insurance. Please step up to the plate on this one and approve this important treatment. Thank you.

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There is a definite category of patients who are resistant to all conventional treatments for depression, including ECT. These patients need something to alleviate their depression, prevent complications and in the long-term have a positive effect.

I have one patient who was able to receive VNS therapy for her depression. Unfortunately, she had some difficulties and the device removed. Interestingly enough, this patient is more depressed now and is sleeping 12 to 14 hours per day. She now wonders if removing the device was wise or if she was being self-destructive. I know that it appears that this device is expensive, but it appears that way only in a short-term basis. By not covering this therapy, you are not servicing a very vulnerable population. I have no long-term experience with the therapy and its impact. However, my 9 months experience with the therapy was not negative and in my patient's own statement, the removal has caused increased depression and excessive sleeping, when all other treatments have remained constant. I hope this information will help you to reconsider covering this device for treatment resistant depression (trd).

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Treatment resistant depression can be both difficult to treat for physicians and debilitating for patients. Most clinicians have had the patient who just does not respond to medication. The arrival of Vagus Nerve Stimulation is important because it is another tool that we can use to help these patient's regain their lives. We know from STAR-D trials that treating these patients with medications yields only 10-20% remission rate at best. What happens to the patients who just don't respond to medication? Currently they are referred for ECT treatment and thankfully it has proven effective for many patients. However, I believe our patients should be able to have a choice whenever possible. Whether or not to use VNS for the patients that haven't responded to more conservative care should be a decision left to the patient and her doctor. Obvoiusly this is not for every patient and I don't think anyone would argue effectively that it is, but patients who have tried all else and failed should be given every opportunity to get better. We would not dream of limiting an accepted cancer treatment for a hard to treat patient because of cost, and it is apparent to me that this is what is happening. Psychiatists must continue to advocate for our patients and educate our law makers that mental illnesses are real medical problems, not deficits of character or spirituality. It is yet another example of the stigma that patients with mental illness must but should not have to overcome.

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I have been a psychiatrist in the private practise of general adult psychiatry in Spokane ,Washington for 28 years. Approximately 15% of my ongoing practise consists of patients with very treatment resistant depression. Most have tried almot every conceivable pahrmocotherapeutic option as monotherapy and usually as multiple therapies, electroconvulsive therapy often for repeated induction series and prolonged maintenance treatment, and extensive psychotherapies of various sorts fronm various practioners. Some have suicided and many are chronically at high risk for suicide and their quality of like is miserable and comparqable to that of very medically ill patients. I have had three patients recieive VNS. One was in the orginal research project some five years ago and, after over 10 years of chronic severe depression, she has since about one year of her VNS implant been relatively free of depression. The other two had implants in September 2006 and both seem to be doing better overall although it is too early to be sure. I know there are limitation to the pivotal long term efficacy study comparing effect of VNS to an independent sample of patients receiving treatment as usual, but I do feel that study adequately demonstrates statistically significant improvement in this very treatment resistant population and efficacy simialr to VNS in treatment resistan epilepsy and often better than efficacy of many cancer chemotherapy regimens all of which are covered by medicare. Given the expense and ethical limitations of conducting more definitive efficacy studies of VNS, I fear it will be impossible to gather more data on VNS efficacy until insurance carriers start covering it which will then allow clinical practice studies to be conducted. I feel VNS provides very real hope for severely suffering treatment resistant patients and they deserve access to this treatment. They ceertainly deserve such access as much as patienst getting vns for treatment resistant epilepsy or cancer chemotheraqpy. I would also add that many of these patients are receving up to monthly maintenace ECTs which alone (not counting medication expenses and session costs) end up being as expensive for medicare in 2 to 3 years. Thank you for considering my opinions. Mark Chalem

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I am a Registered Nurse who works on an inpatient psychiatric unit and also for a psychiatrist in his out patient office. I have seen the stunning results of two patients treated with the VNS implant. One woman who had multiple courses of anti- depressent medications finally under going ECT with no avail until she finally tried to kill herself by lying down on the rail road tracks. The woman lost her leg. As a last resort she had the VNS implant. This woman is now back to work, enjoying life, writing poetry, and has been maintained out of the hospital on an out patient basis. The second patient that I've been involved with is a 19 y/o girl who failed multiple medication trials, had the VNS implant and is now back to college functioning at a much higher level with less periods of depression and has remained out of the hospital. Contrast this with comments made by administrators of the hospital where I work at the VNS presentation where they asked point blank, I can count on these patients for three or four admissions a year, how is that going to affect my bottem line? I am sure that the drug companies are also against anything that they feel may cut into their profits, but this patient population has already failed multiple drug trials, they have nothing left. For the government on one hand to approve the device and then on the other to deny to pay for it is a travisty. As far as it not working or failing clinical trials, the same can be said of drugs, the companies themselves don't know how or why they work and have told you so. Can we attribute all their successes to spontaneus remissions and next have the government deny them. It would save a ton of money since SSRI's are the most prescribed drugs in the US.I think that the cost savings of keeping the TRD patients out of the hospital, as well as increasing their quality of life more than justifies the initial high cost of the implant. Once the implant has become a routine procedure I'm sure the price will come down also. I do not know how much information you reqire but if you need more please e-mail me. Thank you.

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I can not believe the response that CMS has publically announced as it relates to a non coverage draft policy for VNS therapy and treatment resistant depression. The committee that reviewed VNS therapy for people with depression should be ashamed of themselves for implying that the tools for assessing depression are inadequate and that the existance of depression and the existance of treatment resistant depression can not be defined. Millions of people suffer from depression. Over 4 million suffer from treatment resistant depression. These numbers are far to great to deny the existance of the need for adequate treatment. These number should imply that the treatments we currently have been using are inadequate.

In the field of medicine pain is a well known and accepted phenomina. We can't see pain. We can't test to see the level of pain. There are no scientific tools to say that certain occurance elicit certain levels of pain. If five different people break their arm in the same way, there will be five different descriptions of what the pain feels like and five different descriptions of the level of pain the people are experiencing. Yet we would all believe that the person is experiencing pain. That is because we all know what pain is. We have all experienced it ourselves in one way or another. However, we have not all experienced severe or chronic depression. Does that mean that it does not exist? Does that mean that because people respond different to things that happen in their lives that the tools to measure depression are inadequate? No, it does not.

I am sure that you would all agree, that the person who is experiencing pain with the broken arm should be allowed to recieve pain medication and even surgical intervention if needed to relieve their pain. One patient may need Tylenol #3, another Demerol, another even Morphine, while anothr may require surgical intervention. While all of these treatments are Medicare covered and accessable for people with pain to relieve their suffering, all of the FDA approved treatment options to relieve suffering for people with depression are not.

So why aren't the people in the field of psychiatry given the same respect. Why aren't the patients who suffer from depression given access to all FDA approved treatments to treat their illness? People who are suffering from depression should have all FDA approved treatment options available and covered for them just as those who suffer from any other type of pain or debilitating illness would?

The tools for identifying depression explore more depth of the suffering than those of other types of pain. The depression assessment tools such as the HAM-D are recognized and accepted by the field's organized governing body with the APA. The pain from suffering with depression has a mortality rate that far exceeds the mortality rate of suffering from any any other type of pain. Yet people with depression are not given the same opportunity to have access to all FDA approved treatment options to eliminate their type of pain as those in any other field of medicine. Simply put this is discriminitory to the citizens of the UNited States who suffer from depression.

Defining Depression: Although the response committee tried to devalue the field of psychiatry and deny the presence or existance of depression, we all know that there is a difference between having a bad day that results in a grumpy mood versus the patient that can not get motivated to get dressed, go to work, or be active in their family activities. The FDA approved indication for VNS therapy alone defines Treatment Resistance Depression as the failure of "4 or more adequate anti depressant treatments". Dr. Michael Thase from the Univ. of Pittsburgh and Dr. John Rush from the Univ. of Texas Southern had an article that was published in the Fourth edition of Psychopharmacolgy Chapter 92 in 1995 that defines what treatment resistant depression is. The information even shared a table that has staging levels 0-5 of what treatment resistant depression is. In the table 0 is that the patient has not had an adequate trial of medication, 1 is non response to a single adequate monotherapy trial, 2 is failure to respond to two different adequate monotherapy trials, 3 is stage two plus failure to respond to augmentation therapy, 4 is stage three plus failure to respond to a second augmentation therapy, and 5 is stage four plus a failure to respond to ECT. If a person has tried all of these treatment strategies how could they possibly not be identified as treatment resistant. Furthermore, there are 119 references sited in the bibliography of this chapter alone that define what treatment resistant depression is and support the existance of this chronic and debilitating illness that is difficult and costly to treat.

Reasonable and necessary: How can the idea that a therapy such as VNS therapy that has over 40,000 people implanted with a 0% mortality rate be considered anything but reasonable. It is a therapy that has controllable side effects with the use of the magnet and changes in dosing, there are virtually no risks for serious injury that the committee suggests, there are no risks for metabolic or systemic compromises, it does not interact with other treatment options available to the patient, and the side effect when present usually decrease over time.

Necessary treatment: Is it not necessary to reduce health care costs to tax payers? Cyberonics is asking for Medicare coverage for the most difficult to treat patients who have been or are candidates for ECT and/or have been hospitalized. It should be the intended due diligence on the part of the committee to offer therapies that can reduce the health care costs of this difficult to treat and expensive to treat popultation of patients. In the Journal of Clinical Psychiatry 2002;63:963-971 Dr. William Crown et. al. concluded "Those with treatment resistance made more extensive and costly use of medical services, both depression related and general medical" than those without treatment resistant depression. In fact the average additional cost for the treatment of these patients exceeded an average of $30,000 over a five year period of time. Considering that VNS therapy has a 50% reduction in depression scores in 30% of these very ill patients and at least a 25% reduction in 56% of these difficult to treat and expensive to treat patients, it stands to reason that health care costs would be positively impacted.

In summary, I think that it is a shame that the rough draft policy is a negative stance for the people who suffer with depression. I have seen it already changing the lives of most people who have the opportunity to get it. It is a shame that those who could not otherwise afford it are not offered coverage for a therapy that gives 56% of those who suffer an opportunity to improve their quality of life and possibly become tax paying citizens again. There are far too many articles and studies that support the existance of both depression and treatment resistant depression to deny that it exists. VNS Therapy is a safe and effective treatment that should be available to those who need and want it to improve their quality of life.

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I am a pyschotherapist in private practice and have 25 years of experience dealing with individuals suffering from depression. At this time I am treating an individual with treatment resistent depression who has received the VNS. It has been a long journey for her and her family. As the VNS offered the last bit of hope for her after another failed suicide attempt, family members gathered their financial resources and solicited other financial support to pay for this surgery. I am delighted to report that after 6 months there is some notable improvement in her condition. The emotional and financial strain on the family has been tremendous. She is still waiting to hear whether she will be reimbursed through her insurance.

For those without access to financial resources it is a crime to deny this proven effective treatment for depression. The cost of repeated hospitalizations, loss of work,increased cost of multiple medications in an effort to stabilize a patient's condition is far greater than the cost of the VNS.

I urge you to reconsider your decision regarding the reimbursement for VNS. The benefit to the greater community is at stake.
Thank you

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February 9, 2007

Beverly A. Lofton, MHA
Centers for Medicare and Medicaid Services (CMS)
Ref: NCA for VNS for TRD (CAG-00313R)
C1-09-06
7500
Security Blvd.
Baltimore, MD 21244

I am a psychiatrist in private practice in Asheville, North Carolina. I went through medical school at Duke University, served 12 years in the US Air Force as a psychiatrist, and have been in private practice here now for 10 years. I treat a wide range of psychiatric illness and see a particularly large number of patients with chronic severe depression. For the last 10 months I have been referring select patients with particularly severe treatment-resistant depression for surgery and subsequent Vagus Nerve Stimulation (VNS) therapy. So far I have had 20 patients implanted with this device. All of these patients have had severely debilitating symptoms. Most have had marked depression for three or four decades with virtually no relief of symptoms. They have had recurrent psychiatric hospitalizations, numerous ECT treatments and an average of 10-15 trials of antidepressant medication without sustained effect. They’ve carried a profound sense of hopelessness and despair. All have either attempted suicide or have had persistent and strong suicidal thoughts.

I initially was somewhat skeptical about whether this treatment would truly help my patients with severe depression. I have tried to be somewhat scientific about this and have been collecting demographic data and depression scores both pre-and post-stimulation implantation. Most patients have taken a few months to respond, but nonetheless I have been impressed at the powerful effects. Of the patients we have implanted with Vagus Nerve Stimulation Therapy a marked 75% have had a strong therapeutic response. This stands in stark contrast to the quite disappointing treatment as usual response of 10-13 % reported in the literature (and seen in my practice as well) for severe treatment-resistant depression (D04). I realize it may not be fair to fully compare these two cohorts, but nonetheless it feels quite significant in my office.

One particular patient of mine had 40 years of severe disabling depression, had cut off all relationships and been a virtual prisoner in his own home for years. He had gone through numerous medications, hospitalization and ECT without success. After six solid years of weekly psychotherapy with me and countless failed medication trials I had virtually given up hope of his recovery. One month after activating his vagus nerve stimulator he was brighter, more energetic, joined two separate social groups, and began his first dating relationship in decades. I was astounded at the rapid improvement and am convinced VNS was the primary factor.

I recently read through your memo of proposed noncoverage for VNS. I am truly impressed by your committee's thoroughness and deep grasp of statistical analysis. I will never hope to understand statistics and research design as completely as you all. I am a clinician who sits at his desk and endeavors to listen to and help a dozen or so patients a day who are struggling with deep demons in their lives. My tools have been psychotherapy, medication, ECT and for the last year VNS. Of the 20 patients we’ve implanted the majority have had radical turnarounds in their lives that I had not seen for the years I had been treating them before. Most of the responses took about six months and required higher stimulation parameters (1.5-2.0 mAmps). I'm not surprised that D02 found little response at 10 weeks. In my experience this is too early and somewhat under dosed.

I was much more impressed by the D02/D04 comparison data. That study mirrors much better the clinical scenario I deal with in my patients. The results of VNS nearly tripling the response rates in the D02/D04 comparison actually underestimates the robust clinical effects I have been seeing.

I read your numerous criticisms of the D02/D04 comparison and you are probably correct in most of the specifics of your criticism. I wonder, though, are you causing the demise of a potentially life-saving treatment by such a strong condemnation of it. Would Medicare recipients benefit from a more reserved caution regarding VNS? Perhaps allowing some coverage with substantial restrictions would allow the most needed patients to still get treatment and allow the research institutions the ability to design and implement studies more to your liking.

I can only say what I have seen, which is an impressive number of depressed patients near the point of suicide that have turned a corner and have been given a new lease on life. I hope you may be able to balance your desire for stringent research design with a compassion for patients suffering with severe depression. Please consider restraining your abandonment of this treatment and allow it to move forward to some extent and permit broader study and hope.

Thank you for your consideration of this.

Sincerely,

Steven Buser, MD
Psychiatrist

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Please give thought and consideration to those who have resistent depression and need the option of VNS. Mental Health issues are always placed on the back burner compared to other health problems. So often and for so many years, patients w/ depression have been treated as less than sub-human and certainly not considered highly contributing members of society; though many patients suffer a lifetime of working high-level and stressful jobs and caring for families, while trying to pretend and/or hide the pain of many waking moments. Equal rights continue to be a struggle for so many. Yet,in the United States of America,in the year 2007, those with mental illness continue to fight for their rights. Many have no one to speak for them and many remain too embarressed to speak up. Please do the right and courageous thing and approve Medicare for those who do not have private insurance. As both a health care worker and VNS user, I ask you to please stand up for those who have much to offer and work so hard to validate our importance and our contributions to society.

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It is difficult for anyone, a physician, a nurse, or even a compassionate person to grasp the depth of where and how deep a pit depression can take someone until they live with a spouse or experience it for themselves on a daily,weekly,monthly and yearly basis. It is awakening in the morning or from a nap and experiencing the horror that you are alive and stuck in your body with a profound sense of saddness and hopelessness. Frustration cannot begin to describe knowing you have another day ahead of you to get through. You have tried every medication and combination of treatments to help alleviate the symptoms that "happy people" have no clue what you are describing to them. To know there is a good option out there waiting to try but you don't have the money to pay for it is like knowing there is a cure for polio however only the very richest people can afford it or worse yet there are a few people who sit and judge whether or not it should be made available for everyone. That should not take place in a democratic society. It sounds like the medival times or third world countries where warlords hoard money,food,vaccinations from the poor,starved and sick. What is going on? Is there no way possible for our cumulative voices to be heard?

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I think it is unfair to make a unilateral decision for everyone covered by Medicare. There are many people who feel they have tried every available treatment for their depression and have little to no hope they will ever be “well” or even functional again. VNS offers hope to the hopeless. Why eliminate what ultimately could be someone’s last hope for living with treatment resistant depression.

In my opinion, it is direct proof of the lack of legitimacy given to depression as a disease! WHY???

For most people who suffer from depression, medication and treatment are enough to manage their disease. For the few who don’t respond to traditional treatment, VNS presents an option where there wasn’t one. For many, it’s their last option! Why take that away from everyone on Medicare? Instead, why not set up some specific guidelines that must be met before VNS is considered?

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In regards to the decision to not cover the DNS for depression I continue to be disappointed that a reasonable treatment is being denied to New York State citizens that have Medicare.

As a clinician-researcher I understand the need for prospect is and control data. I also understand that the peer reviewed data that we have now is reasonable and shows an effect in a case-control design. This is apparently adequate for Canada and Western Europe. I also find it frustrating that certain regions and United States allow VNS and others do not in regards to Medicare coverage.

My clinical experience with the VNS device is that it works very well in one third of my patients and not at all and another third which is reflective of the peer reviewed data. I've seen patients with completely refractory illness get back when other medications, psychotherapy, shock treatments have failed.

In short, I agree with the scientific merit of doing better, prospective controlled studies which I understand are underway. I also understand that there is reasonable data to show effectiveness of this device in a population that is desperately seeking new treatments that can allow remission of depression. Many cancer patients are allowed compassionate use treatments and treatments that have less data than that currently at hand to treat their terminal illness. Depression clearly has a suicide rate greater than 10% so I would consider some of my patients terminal and in need of treatments even if there is not perfect data. If there is reasonable data we should proceed, therefore I disagree with CMS opinion to not allow VNS for depression.

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As a psychiatrist and teacher of psychiatry for the past 35 years, I am shocked by the non-coverage decision for VNS.

Treatment resistant depression is a debilitating and often fatal illness. By definition, all patients who meet FDA criteria for VNS have failed all other reasonable treatments. At least 30% will respond robustly to VNS. This is being viewed as an inadequate response to justify coverage. Imagine 100 patients with MS severe enough to confine them to wheelchairs. Imagine VNS will enable 30 of them to walk, and of those 30, 20 will run! Would this be seen as poor response or nearly miraculous?

In addition to depriving Medicare patients of coverage, this decision will be used to deny coverage by private insurers.

The FDA has reviewed the scientific data. They have approved VNS. While refusal of payment coverage is not the same as removing VNS from the scene, it will do the same thing practically, and patients will die as a result. This decision is bad public health policy and immoral in its treatment of the mentally ill. It should be reversed.

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I am a psychiatrist and have had two patients implanted with this device for treatment resistant depression. They have generally tolerated the procedure very well, and they have tolerated the treatment. One individual has been on disability for years, but within a few months of the implant has improved to the degree that he is now actively looking for work. The other individual has been on disability for many years. She has had the device for a few months and the intensity of her depression episodes has been less. With the likelihood of response to additional trials of medications being so poor after they have been on 4 or more medications, the data for VNS looks pretty good. I do not see why this should not be an approved procedure. I would think that it could bring significant cost savings to society in treatment costs and reduced disability. Thanks

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As a psychiatrist in private practice it's no doubt the most challening patients we see are those high utilizers of health care dollars, the treatment-resistant depression patients. They have multiple increased costs regarding inpatient care, medical comorbidities, as well as medications and complications from those medications. VNS is not for everyone but it is an option that should be available to that select group of patients. The biggest concern is cost. I would hope MCare would not deny in hopes that Cyberonics would falter and become an easy takeover target for a larger medical device manufacturer, e.g. Johnson & Johnson, but if it did, I would imagine the larger economy of scale might result in a lower device cost and therefore make it even more palatable to the bean counters at MCare. I have five patients with the device - four I have been with from the start, and most all now over a year's experience with the device. It has been life changing for 80% of them, life changing. Please help us help these patients. If nothing else, allow it under stricter criteria. As the world knows, "As Medicare goes, the privates follow." and this would be an enormous tragedy.
Regards,
John Latz, MD
Private practice psychiatry
Mooresville, NC

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Dear Centers for Medicare and Medicaid Services

I am the Director of the Vagus Nerve Stimulation (VNS) Service at the Massachusetts General Hospital. I am writing to strongly disagree with the preliminary noncoverage decision by CMS regarding the use of VNS in treatment resistant depression (TRD).

The available data regarding VNS suggests that the response and remission rates are markedly higher with VNS when compared to continued antidepressant trials (treatment as usual, or TAU). The response and remission rates with TAU are very low and are congruent with the rates seen in the STAR-D study. In fact, the TAU response and remission rates in the VNS studies are even slightly lower (not surprising given that only TRD patients rather than all depressed patients were studied). The response and remission rates with VNS were 2-3 times higher than TAU. Depression is a serious debilitating disorder. The WHO ranks it as the fourth most disabling conditon. If a new chemotherapeutic agent were available that treated a specific neoplastic disease with response and remission rates 2-3 times higher than previously existing treatment, it would be easily covered (probably even with less data than is available for VNS in TRD). In addition, while the noncoverage decision quibbles with statistical issues in these data, the quality of the data are comparable to data used for approval of psychotropic medications for depression. I cannot, for the life of me, understand the logic behind this noncoverage decision.

In conclusion, I wish to strongly encourage you to reconsider your noncoverage decision for VNS for appropriate TRD patients.

Please do not hesitate to contact me if you have any questions or concerns.

Sincerely,

Darin Dougherty, MD
Director, VNS Service
Co-Director, Neurotherapeutics Division
Department of Psychiatry
Massachusetts General Hospital

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As a clinical psychiatrist who has been in private practice for over 21 years and who specializes in Treatment Resistant Depression, I strongly oppose the proposal for the Draft National Coverage Policy to not cover VNS for TRD. I am currently following 11 patients who have had this proceedure done and I see the Positive benefits that VNS has had on the vast majority of these people; I even have 2 patients who are in full remission from their chronic, formerly intractable major depressions. Are you not aware that major depression kills people every day, that it is one of the major reasons for people having to take time off work or go on disability, it causes multiple hospitalizations and ER visits, it disrupts families, it requires multiple office visits/therapy visits and the medication costs are astronomical for chronic depression. All of my patients who have had VNS implantation surgery done, formerly had been tried on multiple psychotropic medications(at appropriate doses & for approp. durations), some had been hospitalized, some had gone through trials of Electroconvulsive Therapy, most had to go on disability. All of these patients were formerly c/o symptoms of hopelessness, helplessness, worthlessness, lack of pleasure in life, moderate-to-severe depression, some with wishes to die or suicidal thinking. Don't you see, the VNS therapy(now approved by the FDA since 7/05) gives hope to people who are without hope. Follow-up studies and my own clinical experience show that VNS can be effective for TRD when nothing else has worked. I urgently ask that VNS coverage be allowed ASAP. Thank you for your time and consideration.

Sincerely,
James R. Hicks, M.D.
Phoenix, AZ

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Disclosure: I am on the speakers bereau for Cyberonics. My investment portfolio includes the publicly traded stock of Cyberonics. (NYSE symbol: CYBX)

Dear CMS,

Thank you for the opportunity to make this comment. I am an epileptologist with more than a hundred patients in whom a Vagus Nerve Stimulator (VNS) has been implanted for seizure therapy. Although I was initially somewhat skeptical, I was very impressed by its effect, particularly for patients with tonic seizures. My first patient (1997) was falling several times a day until he had the implant. He then practically stopped falling until he ran out of his battery. He has since stopped falling after replacement of the unit except occasionally. He probably would have made many ER visits, if it were not for the VNS therapy.

Since then, I have had many patients return with good results to my clinic. I have had only 2 or three people request the removal of the device due to lack of efficacy or discomfort. Of the more than one hundred patients I follow, most patients had the seizures documented by video EEG, except in cases where the patients came to me from another facility. Of my own patients, that I lead the implantation, I have at least five patients that are seizure free and may where the patient and the family are satisfied with the current seizure control. I have only less than a handful of patients who did not have acceptable improvement in their seizures. Even they prefer to continue using it.

I have also noticed improvement in depression in some of my patients where depression is a co-morbidity. If the results for seizures in my post FDA approval experience for the treatment of seizures is any indication, compared to the pilot studies for epilepsy, and the situation is similar for depression in the future, VNS therapy would be a significant improvement in our therapeutic options for depression.

If you need additional information, please feel free to contact me.

With Best Regards,
K.J. Oommen, M.D.

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February 7, 2007

Dear CMS,

I am a vascular surgeon. I implanted 16 Cyberonics Vagus Nerve Stimulators in 2006. Patients tolerate the procedure very well. All have had the procedure as outpatients. I admit to having some skepticism about the use of this modality for depression. I have been amazed by some of the dramatic changes in mood experienced by these patients even in the short term. I recommend that you reimburse for this indication as you have for the epilepsy indication to provide better access to the treatment.

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If we have the ability to provide another treatment option to individuals with treatment resistant illnesses such as depression why wouldn't we?

Depression is a challenging illness to deal with as it is something that no one can really see the effects of or understand the depths of except for the person dealing with it. Now add on the burden of seeking help through traditional medications, but not getting any relief-finding out that your are treatment resistant. The despair must be overwhelming. All you want is to lead a normal life. You desperately seek out other options to help. A treatment such as VNS not only represents an alternative, it represents hope. And without hope, what does one do?

So I ask again, if we have the ability to provide options to individuals with treatment resistant illnesses such as depression why wouldn't we?

Thank you for the opportunity to comment.

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February 7, 2007

Comments on CMS proposed decision “…that vagus nerve stimulation is not reasonable and necessary for treatment of resistant depression.”

First, I appreciate the attention your group has paid to difficulties in defining depression, treatment resistant depression, and assessing treatment outcome. However, I do not think this effort gets to the point of the main question: If a depressed patient has failed 4 or more treatments that have been adequately administered, what treatment(s) might next be administered to better this person’s mental condition? Indeed, the D-04 study, of which I am the author of one of the manuscripts, paints a very bleak picture for available treatments (pharmacotherapy, psychotherapy, poly-pharmacy, and electroconvulsive therapy) to provide a meaningful rate of improvement for such patients, and those who did improve did not evidence sustained improvement. Vagus nerve stimulation therapy, in comparison, provides a much better outcome for such patients, and those who do improve sustain their improvement.

I wish to point out that the main areas of “imbalance” between the D-02 and D-04 populations (see p. 31 of 37 of the report) would seem to favor improved outcome in the D-04 population as compared with the D-02 population. Indeed, more D-02 than D-04 patients had received ECT during their lifetimes and during their current major depressive episode. The difference in ECT treatment history would indicate that such patients had a higher degree of treatment resistance and would be less likely to respond within a follow-up period. If they had responded to ECT, they would not likely have sought treatment with VNS.

Secondly, the higher percentage of patients who had multiple episodes of depression (10 or more) in the D-04 than the D-02 group would also favor such patients having a greater chance of improving over a follow-up period, since they had shown a history of periodically improving in the past.

Thus, both of these “imbalances” would favor improvement in the D-04 as compared with the D- 02 group. Indeed, the D-02 group showed greater improvement, and greater sustained improvement, than the D-04 patients in spite of the imbalances which would seem to favor a contrary outcome.

The arguments raised about difficulties with rating scales measuring depression are quite true; however, remission is easily measured by all ratings scales, by the clinician, by the patient, and by the patients’ families. The number of public comments to this point reflects the improvement noted by patients and their families in the treatment of chronic, refractory depression, and this is perhaps the best measure demonstrating efficacy for VNS. The public comments did not, apparently, include comments from individuals who were treated with other available treatments (“treatment as usual”) noting their positive outcomes—the D-04 data support the notion of continued difficulty in achieving a satisfactory outcome with “treatment as usual”.

I realize that you discount case reports, but my clinical practice involves assessing patients with treatment resistant depression and recommending subsequent treatments for them. Defining treatment resistant depression in a patient who has failed multiple treatments is not a difficult clinical task, but is obvious. Recommending treatments which might be of benefit is difficult, and having VNS provides an important treatment option for such people. Recall that VNS is not recommended for individuals who have failed only one treatment, but that this treatment is for individuals who have failed 4 or more adequate treatment trials. This population is clearly in need of treatment options, and I hope you will reconsider the decision not to provide Medicare/Medicaid coverage for such patients.

Sincerely yours,

David L. Dunner, MD, FACPsych
Director, Center for Anxiety and Depression
Professor Emeritus, Department of Psychiatry and Behavioral Sciences
University of Washington

Center for Anxiety and Depression
7525 SE 24th Street, Suite 400 Mercer Island, WA 98040

I have research grant support from Cyberonics and have received travel support to attend meetings from Cyberonics.

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I am a practicing Neurologist who has now had two patients with VNS implantation. One patinet has had a dramatic response in terms of seizure reduction, and while stillon medication, has gone for 3 weeks without a seizure, which is the longest that he has ever done so. He had staph aureus meningoencephalitis as a child, and subsequent seizures and mental retardation.

The second patient has long standing generalized seizure disorder, and is intolerant of many medications. He has had trouble with hoarse speech with the VNS stimulus, and is at a low setting, without benefit yet.....

I do believe that VNS is well-tolerated, and should be covered for any disease state for which it is found to be effective or FDA approved.

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I am a board certified psychiatrist whose specialty is the treatment of individuals with Treatment Resistant Depression (TRD). I coordinated the implantation of VNS for 10 individuals with TRD who all failed ECT the "gold standard" treatment for TRD. All 10 have tolerated the initial implantation and titration and most have significantly benefited from this treatment. The average Beck Depression score in this group before implantation was 41.3 and now is 17.0 with clinically significant improvement in functioning and most feeling that this has been the best they have been for years. In addition, self-esteem improved as well. One individual was able to get a job and another completed a semester of college for the first time since becomming ill. Please don't take hope away from other patients I am working with who desperately need this FDA approved (the only treatment to show benefit in RCT's for this population) life saving treatment.

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I am a child neurologist with a major interest in the treatment of epilepsy. I have experience with the use of vagal nerve stimulation (VNS) in over 200 chilodren with medically refractory epilepsy. Side effects are almost nil. Almost half my patients have have reduced their seizure frequency by 50%, and 19% of these patients have at least a 90% reduction in seizure frequency. (See;Arch Pediatr & Adolesc Med 2003;157:560-564.)

The benefits are very similar in patients with treatmenbt resistant depression (TRD). Like patients with epilepsy, patients with TRD should have available this relatively benign intervention, as opposed to potentially injurious medicinal therapy, or recurrent electroshock treatment.

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It is unconsciousable to deny people access to treatments that might work. It appears that the decision makers at CMS have not endured the agony of long term major depression otherwise you could not sleep at night with decisions such as this - denying access to VNS. Saving one person's life... isn't it worth it? If it is safety you are concerned about I suggest you encourage some studies on certain forms of yoga breathing exercises which stimulate the vagus nerve. India has been doings formal studies on this for years. Please check out the book, Yoga for Depression, by Amy Weintraub. It takes time and committment to do these everyday but I'd choose it any day over the severity of VNS.

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I am a Staff Psychiatrist in an underserved area of Missouri. I have at least 3 patients that are under consideration for VNS therapy for Treatment Resistant Depression. There are many others who spend countless dollars more in ER visits, failed multiple medications, and multiple hospitalizations that could benefit from this cost effective procedure. It is clinically proven to work for the sickest patients. Please reconsider keeping VNS as an important, life saving treatment possiblity for patients.

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I am an epileptologist in southern Maine. I treat patients with pharmacoresistant epilepsy. I have personally managed over one hundred patients with the VNS. Approximately half of these patients have comorbid depression. Two thirds of my patients with comorbid depression and refractory epilepsy with the VNS have had a dramatic improvement in mood/depression scores and QOL scores. Many have come off there antidepressant medications. None of these patients had TRD, but since VNS is the only FDA approved treatment for TRD and since the alternative treatment is electroshock therapy, it seems odd that Medicare beneficiaries would not have access to this potentially helpful intervention. I hope you reconsider coverage for the VNS in patients with TRDparticularly in those with comorbid epilepsy!
Sincerly
Heidi Henninger, MD

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Please reconsider the determination to deny coverage of VNS therapy. There are many thousands of treatment-resistant depression patients who cannot or will not accept ECT. The VNS device has extensive use already in the treatment of epilepsy patients, and has proven to be safe and effective in that population. My clinical experience in the one patient who received it last year is very favorable, without any hospitalizations or suicide attempts since introduction of the device. I have 4 candidates who are appealing the denial of coverage of implantation of the device, and until this issue is resolved, I have not felt it is ethical to suggest it as a source of hope to other suffering people. Please contact me for further information if needed. Thank you for your attention. Sincerely, Joseph P. Arisco, M.D., DFAPA

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While the debate on the treatment of Vagus Nerve Stimulation for the Treatment of Resistant Depression is important, I wish to add my observations.

I have one patient who has had the surgery and is showing improvement with treatment. I have only one patient with this device. I have many other patients who do not respond to or tolerate medications and other treatments for severe depression.

It is important to offer Vagus Nerve Stimulation as treatment option to these patients.I recognize that it is important to show statistical improvement. This is scientifically important.

However, the science has demonstrated that there is a population of patients with severe depression who benefit from this treatment.From a clinical standpoint it is important to offer effective treatment to those who require it. Further study will help define which patients are most likely to benefit.I oppose the proposed CMS non coverage position, and I recommend reconsideration for CMS coverage.

I have no financial affiliation, nor financial gain for CMS coverage. I am concerned that non coverage will lead to denial of this treatment and therapuetic nihilism for recovery from severe depression.

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Dear Sirs, As a practiciing physician in the field of psychiatry I was very happy that the FDA had approved VNS as there was little hope for people who suffer with the mentally crippling disorder of Major Depression that is refractory to standard treatment. With the advent of VNS, there was hope. In reality, I have witnessed lives turn around,people turn away from suicide and despair after the VNS implant. I hope that we dont lose access to this very powerful treatment option that saves and transform lives. Medicare should offer this treatment as it is as necessary to the depressed as insulin is to a diabetic and dialyisis to the renal impaired sufferers. Medicare shouls not have a double standard.

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I believe we need to cover this for our Medicare patients. VNS has been a tried and true technology for nearly 10 years now for epilepsy and has documented antidepressant effect. Treatment resistant depression is a neurological condition with brainstem pathology resulting in decreased output from the raphe nuclei and the locus coeruleus, which causes the well-documented reduction in serotonin and norepinephrine associated with mood disorders. VNS is known to act by stimulating these areas. Without VNS, the up to 25% of patients who do not respond to SSRI or SNRI drugs are left with only ECT which is not a long-term solution for these patients and has significant impact on short-term memory. VNS is the best option I have seen for restoring a patient to function and quality of life. I urge a decision in favor of coverage of VNS for TRD.

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Please reconsider your intentions of noncoverage for this important treatment. I have already encountered a few patients who were perfect candidates for this treatment but were denied coverage. They were devastated since they had failed numerous medications and were not prepared for ECT. This treatment is often seen as the last chance for a severely depressed treatment resistant patient. Depression is a very serious illness and this population needs to have access to such novel treatment options.

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I took an oath to #1: do no harm, and #2: try to relieve suffering. Suffering's very definition is depression.

Rarely, one encounters patients whose illnesses are so severe as to intimidate the provider. Patients who have been treated while adhering to an appropriate alorithm for an adequate duration of time and who have had a deterioration raises fear that improvement is impossible. When the illness is depression, one then fears that suicide is the inevitable result of treatment failure.

VNS trials and experiences have taught me that improvement occuring in this patient population is real (not placebo-generated given this group's horrible placebo response rate), SUSTAINABLE, and that IT RELIEVES SUFFERING. Even patients whose symptoms are reduced by less than 50% ("NON-responders") actually report substantial quality of life improvement. Many "NON" responders actually returned to work or reported less suicidality in the trials and in psychiatrist's post-approval clinics.

Honestly, I RARELY see patients who meet criteria for VNS implantation (perhaps 4 or 5 in the last year or two), but I recognize that when I do see them, I have an effective (and COST-effective) treatment option. They utilize services less frequently, and combination treatments, particularly the atypical antipsychotic drugs, are less often necessary.

Access to this treatment is ESSENTIAL for adherence to the ethical principles of beneficence and utilitarianism. Please continue to make this treatment available to our population's most severely suffering individuals.

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I am a psychiatrist as well as clinical professor of Neuroscience at UND Medical School. I have practiced psychiatry for 18yrs and have no financial affliation with VNS. I have two patients that I have treated for the past 15yrs for treatment resistant depression (one bipolar depressed, the other MDD). After only partial response to aggressive medication + psychotherapy over the years, brief partial response to ECT in the past, we have chosen to pursue VNS to attempt to impact on their chronic depressions that have severely impacted their lives. We have struggled to find insurance approval, after 8 months was succesful to implant the 1st patient, she is now 8 months into the treatment and has had a modest response, lowering her Beck Depression Inventory's by 15pts. The 2nd patient will be implanted next week, unfortunately for her, we were never able to get insurance approval and her family has decided to self fund it (likely approaching $80,000).I do believe there should be careful oversight of which patients could get the VNS but on appropriately selected, true treatment refractory patients without substance problems or other confounding factors, I think it should be available as a treatment option. I would hope that it is rarely used but that it would be available for this select group of suffering patients.

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I am srongly in favor of covering VNS for treatment-resistant depression. Major Depression is one of the most disabling conditions in medicine. I consult on over 100 treatment-resistant patients yearly for other psychiatrists. I know full well the social and economic impact severe depression has on our patients. I also know the limitations of medications which has been amply documented in the scientific literature. Many of the patients I consult on will receive ECT. This is a powerful treatment for severe depression , yet not all patients respond, some are afraid to have it done and some do not like the side-effects. I personally have treated several patients with treatment-resistant depression who have had vagus nerve stimulation done. I have been quite impressed with the overall positive response these patients have shown. The enduring nature of the response has also been impressive. These patients had all been treated with adequte trials of many different medications, psychotherapy , and , in several cases, ECT. This group of patients is different than the population usually seen in acute pharmacological trials in that they do not have a high placebo response, especially one that continues for months on end. The pulse generators in my patients have been well tolerated. My reading of the literature tells me that there is a substantial population of patients who will respond to VNS who might otherwise continue to suffer the misery of chronic depression. The one short-term study does not seperate from placebo. However, that is not surprising as it takes longer to obtain a sustained positive effect, which is clearly seen from three months on. I have displayed a poster at a scientific meeting and am revising an article to publish outlining the overall course of treatment for one of our patients before and after VNS. The social and ecominic benefits to the patient are clear. Why would we want to restrict useful treatment from patients. We should be doing everything possible to help patients function as best that they can and help remove the prejudice and stigma of depression.

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This is a type of therapy that really helps patients with severe and debilitating depression who have failed on other therapies. The change is apparent on follow-up in eyes and faces of these patients. The most dramatic story I have had was of a young woman who had been unemployed for years (and covered under medicaid) because of severe depression. She returned 9 months later for revision of implant migration. She was now working and covered under her employer's insurance plan. Not many treatments help patients feel well enough that they can return to their lives as productive citizens. Most of the patients with treatment resistant depression have lost many days (and even years) of work because of their disease. VNS therapy offers real help and the promise of return to a productive life!

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I was very disappointed that VNS for TRD was turned down for being an eligible option as a paid health care. I wish to state again that in 2005 our Depression Bipolar Support Alliance (DBSA) Aurora Chapter had an Education Night at which the VSN for TRD was presented and well received by the 25 or so attendees. Also one of our members has had the procedure done and last I knew was very pleased. People with Mood Disorders are very much in need of help from the Medical World besides medications!

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As a psychiatrist with an interest in the treatment of patients with treatment resistant depression, I am alarmed by the trend towards non-coverage of treatment with Vagal Nerve Stimulation. I am also an ECT provider, and have a sub-group of patients for whom, to date, ECT is the only treatment to which these patients respond. Given the cost of ECT, the cost of long-term treatment with it may with time dwarf the cost of treatment with VNS, which also holds promise for long-term management and recovery from this disabling disease. Providers and patients are in great need of new treatments with the promise held by VNS.

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Regarding CMS refusal of coverage for VNS for treatment of refractory depression:

1. While the term "refractory depression" has not been "scientifically" determined, failutre of four trials of antidepressant medication would seem reasonable per the FDA defintion and per the results of the STARD trial of antidepressants.

2. While failure to control for placebo response or the natural waxing and waning course of depression is a flaw. This critique of the VNS data appears weak in light of the fact that individuals who had failed four antidepressant trials and who had demonstrated an unremitting course of depression would seem to be a group unlikely to exhibit substantial placebo response or spontaneous remission of depression.

3. Although a pivotal controlled trial of VNS failed to demonstrate benefit, it should be noted that a fairly large body of less rigorous data exist and that the trial in question may have been flawed by the period of followup. That is, data on the antidepressant effects of VNS suggest that antidepressant benefits may require many months to emerge. Thus, shorter periods of controlled observation may not be adequate to detect a therapeutic effect.

4. Given that with the exception of ECT, individuals afflicted with unremitting depression have very limited treatment options, I would hope that VNS would not be excluded from reimbursement without further careful consideration.

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To whom it may concern: it seems unfortunate to me that Medicare will continue to deny coverage of the Vagus nerve stimulator for treatment resistant depression. I would like to systematically address the committee's comments below.

CMS Draft Decision Rational:

RESPONSE: I think that this comment is very misleading. Scientific leaders in the area of major depressive disorder certainly think that treatment resistant depression occurs. For example, Michael Thase and colleagues from the Western psychiatric Institute in Pittsburgh have a clear reading and staging scale for treatment resistant depression, not unlike staging used for cancer or Parkinson's, etc. in the VNS studies, treatment resistance was well defined and the amount of medication trials was very strictly catalogued and detailed, possibly more than any other clinical trial in major depression. Again, I think this comment is incomplete error.

RESPONSE: I do agree that a randomized controlled trial is the strictest design and is often employed in pharmaceutical trials. It is likely next to impossible to design and run a true sham trial in a device that provides voice alteration is a key adverse effect. With this particular device and side effect profile it may be necessary to use a case-control design.

RESPONSE: this is true in that the short-term study failed to find significance on a clinician rated scale which was the primary endpoint measure. It should be noted that a secondary, patient rated scale was clearly significant. The design flaw in the study was that the sham was not conducted over several months. The longer term open-label studies and post hoc case control study, might be a reasonable alternative and is what the FDA considered and allowed.

RESPONSE: long-term, observational data is worth while, but certainly is not a stringent as prospective and control data.

RESPONSE: CMS is certainly entitled to its opinion in this matter. I think if you were to interview and poll leaders in the treatment of major depressive disorder you would find these individuals more accepting of the data and the FDA approval. I also feel that there been other FDA approvals that are less expensive, have less data, and are allowed and paid for by insurance companies and Medicare. I think the other compassionate use devices, medications, clinical applications that are used without question in those with other severe, resistant medical illness such as certain cancers and neurological disorders.

My understanding is that the FDA requested ongoing naturalistic, observational studies and also more prospective studies. If we find that the prospect of studies over time show a statistical and meaningful clinical response in treatment resistant depression, I would hope that CMS immediately retracts the above findings. If it takes two or three years to see this data, and if it is positive data showing the effectiveness of VNS then we will all be deeply saddened by the delay in getting these patients the care they need. I certainly can see the other side and that future studies fail to show an effect, then CMS is right to decline coverage.

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I am a neurologist with special interest in intractable epilepsy and patients with special health care needs. I have a large number of patients who suffer combined effects of intractable epilepsy and intractable depression. These can also be considered as equivalent to treatment resistent epilepsy and treatment resistent depression. It is very important that we as concerned health care professionals have available any treatment method which could provide benefit to our patients with minimal risk. I have been very impressed by the literature on VNS, as well as experience with my own patients, that the VNS offers excellent benefits with minimal risks.

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