Saturday, December 30, 2006

VNS Therapy: Debate Continues

I’ve read comments from a few readers who disagreed with my take on vagus nerve stimulation (VNS) therapy. In fact, we've had a little debate going on for a while. In the comments on the last debate, one reader provided a link to the FDA’s site regarding VNS trials. It can be accessed here. I’ll quote from the FDA review on the site:

“The primary effectiveness endpoint for the randomized, sham-controlled study was an analysis of the percent responders (greater or equal to 50% decrease in HAM-D score from baseline to exit) between the 2 groups. In an evaluable patient population, 15.3% (17/111) of the active stimulation group were considered responders as compared to 10.0% of the sham group (11/110). The difference was not statistically significant (p=.238). [emphasis in original].” There were five other measures of depression and VNS was superior only one of them. VNS batted one for six in its pivotal outcome study.

To put it in layman’s terms, VNS was no better than sham (fake) VNS therapy. Yet this was the main study upon which the evidence for its efficacy rests. Uncontrolled studies seem to yield results of about 20% relapse at 2-year follow-up. Since these studies are uncontrolled, there is simply no way of knowing about how much of the 20% is due to VNS or the passage of time or other factors. Given that the sham therapy produced pretty much equivalent results to VNS, I believe that something outside of VNS is likely producing much of the 20% remission rate.

I understand the desperation of patients who have not found success through a variety of treatments. Perhaps VNS should be made available for some patients, but should insurers and/or the government pick up the tab for an expensive procedure that has such weak evidence of efficacy? Should controlled research emerge indicating VNS works better than psychotherapy, medication, and other alternatives in the long run, then I’ll gladly eat my words. Until that point, I see no reason to get on the bandwagon.

If readers can add something new to the debate, I'll likely jump in. If readers wish to rehash old, already posted arguments, I won't be participating.


Anonymous said...

Thank you for some rationality to this debate. Like you, I want to see properly controlled, scientifically valid studies of efficacy (and cost effectiveness too) before leaping into serious brain surgery. In my field of chronic pain, too often we see people returning after high-cost and invasive procedures that seem to disturb the neuromatrix rather than 'solve the problem'. I am reminded of the title of a film 'As good as it gets' - perhaps our searching to find happiness is leading us astray?

Anonymous said...

Dear Doc,

As I read both your response and that of “adiemus” I am reminded of several points. First, I am reminded of the modern version of an oath which I’ve excerpted and pasted below:

“I will apply, for the benefit of the sick, all measures [that] are required, avoiding those twin traps of overtreatment and therapeutic nihilism.

I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon's knife or the chemist's drug.

I will not be ashamed to say "I know not," nor will I fail to call in my colleagues when the skills of another are needed for a patient's recovery.”

“I will remember that there is art to medicine as well as science.” Please note the word “art” precedes the word “science” and from my own long-time personal observations as well as readings that observations most often precede science too.

With part of the oath cited above I am also reminded as a very, very long-time support person of what I’ve experienced upon several occasions through the years and what I refer to as “Professional Arrogance” and/or “Deity Syndrome.”

In “adiemus’” post he/she speaks of “serious brain surgery” which this therapy does not entail. He/she writes of “properly controlled, scientifically valid studies of efficacy” which I and others would agree with but he/she does not propose or discuss the protocols or the words “properly controlled” to be used for such a study. How does one “scientifically” determine “efficacy” in this patient population? I would appreciate “adiemus” citing any quantitative and/or diagnostic measurements to determine one’s “pain.” Are there any blood tests, X-rays, MRI or other such scans to do so? Do we utilize the same protocols and study criteria for this and all future medical devices of this nature as is utilized for drug studies which is the basis for the controversy and discussions surrounding the original VNS study.

While “adiemus” is reminded of the film “'As good as it gets'” I believe he/she misses the point in this patient population in that these individuals aren’t seeking “happiness” but are in fact trying to reduce their pain, suffering and anguish. With the reduction of pain, in some, is the side-effect of some degree of “happiness.”

Doc, in returning to your recent statements, I’m simply not qualified to properly analyze and/or debate the data on the same basis as you are but I shall take you up upon several points. The first point is the mean age of these patients was 46.3 years and the duration of their illness at the time was 25.5 years. Since you’re the man of statistics would you care to venture the cost of trying to maintain wellness for this population?

From my readings and based upon numerous hospitalizations and emergency care and the like, the figure is about $100,000 per year or more per patient. The figure bandied about is that there are some 4 to 5 million patients figuring into this unique population. Using 4 million as the number multiplied by $100,000 per year, multiplied by 25 years (4,000,000 x 100,000 x 25) yields a cost of care totaling $100,000,000,000,000.

Utilizing your “20% remission rate” multiplied by the same 4 million, multiplied by $100,000 per year multiplied by 25 years (.20 x 4,000,000 x 100,000 x 25) yields a savings of $2,000,000,000,000.

Let’s also reduce from the savings number an initial cost to implant all these patients. We take all 4,000,000 patients x $30,000 (4,000,000 x $30,000) yields a cost $120,000,000,000. Deduct this cost from the saving of $2,000,000,000,000 we still have a savings of $1,880,000,000,000. “That ain’t chopped liver.” Also please feel free to correct any of my quick calculations as these numbers were a little too large for my adding machines capabilities.

Yes I know, there are other items to figure in such as inflation, the costs of replacement implanting over the 25 years, the fact that about 80% won’t be re-implanted etc, etc but one gets the idea that even 20% represents a significant dollar savings. Let’s also not loose sight of the existing discrimination and stigmatization also prevalent in the medical community toward mental health let alone the general public. The more important point in my mind, which I continually try to educate and emphasize to some of you academics and medical professionals is that you in fact tend to lose sight of the patient and the patient’s desperate need to achieve a degree of wellness and not necessarily “happiness” (not a scientific term). I know many individuals not suffering any illnesses financially secure with all kinds of worldly goods, professional achievements and yet unable to achieve “happiness.” It is the very nature of these words and statements that some times lead me to sense this “Professional Arrogance” and/or “Deity Syndrome” not knowing whether one has walked in the shoes of these very long-time suffering individuals, their families and/or loved ones.

As I recall from the comments to CMS (Medicare – National) there were one or two responses from physicians suffering badly from this illness and more than willing to seek an opportunity at a “20% remission rate.” I also find it of much interest that a patient suffering a terminal cancer is often afforded the opportunity, paid for by the health insurance company, to seek experimental treatment yet an FDA approved therapy is denied a different group of terminal patients. Why is that?

I would also like to cite the response of only one of the many professionals who would take exception to your mitigating the significance of a “20% remission rate.” Please read or reread the response of Dr. Scott Aaronson, among many, found in the listed link below:

I do also find it of interest that when so called “scientific studies” are performed and the research papers are issued the number of differences of opinions and conclusions that are obtained by the professionals reading the same data, why is that?

Once again, I do thank you for this opportunity to share and express my views on your forum and while I may be accepting of your personal striving to obtain the ideal and the truth, the reality exists for me that it may well be unachievable for my spouse and other VNS patients and/or prospective patients and that “20% remission rate” is “'As good as it gets'” but we’ll take it. It just may turn lives around as I also have been reading and am personally aware of.

Here’s wishing you and yours and all those that read your forum a very Healthy, Happy, Prosperous and Peaceful New Year.



October1929 said...

Dr. Doc,

For anyone doesn't know how to properly read the pie graph posted on the FDA web site, let me help.

Per FDA:

"Study subjects( evaluable patient population)

Sustained Response

1. Extrordinarily Meaningful Benefit- 10.2%
2. Highly Meaningful Benefit- 20.0%
3. Meaningful Benefit- 25.0%"


Prior to vagus nerve stimulation therapy, the study subjects lived a life of chronic depression, utter despair and hopelessness. Their loved ones were scared and frustrated.

More than 50% of this very treatment-resistant patient population had at least a meaningful improvement in the quality of their life. And de facto, the lives of their family
members also improved.

If a skilled clinician or scientist were to apply these identical statistics to a physical disease that had become incurable, there would be no debate about this safe and relatively straight forward treatment option.

I wish the very best of luck to those treatment-resistant depression sufferers who are withheld awareness of this therapy due to misinformed clinicians. At this point, I think it would be considered malpractice.

Anonymous said...

And the number one reason to be skeptical of the VNS claims is that...

drum roll please....

some, perhaps much, of the work was done by the some of the same people involved in the TMAP.

Adiemus said...

Hmmm, 'Herb' asks me to define 'properly controlled' scientific studies
**He/she writes of “properly controlled, scientifically valid studies of efficacy” which I and others would agree with but he/she does not propose or discuss the protocols or the words “properly controlled” to be used for such a study. **
I would refer 'Herb' to the usual evidence-based sources such as the Bandolier or Cochrane reviews for some of the usual methodological reviews of studies relating to efficacy...
***I would appreciate “adiemus” citing any quantitative and/or diagnostic measurements to determine one’s “pain.”***
I firstly would refer 'Herb' to the International Association for the Study of Pain website for a definition of pain - and to discuss some of the challenges in measurement of this very complex experience.
One of the recent additions to the understanding of pain is that it is more than a simple neurological response - in fact it is a multifactorial, biopsychosocial phenomenon (Melzack and Wall's first publication on the influence of the dorsal horn was published in 1965, and unleashed the vast array of empirical studies demonstrating the influence of descending pathways on pain perception and response).
Therefore most modern health care workers and researchers are aware of the role of distress in the amplification or amelioration of the experience of pain (along with beliefs, attitudes, behaviours, emotions, responses of other people...).
This means it is impossible to measure a pain experience without reference to the individual's experience - with our current state of the science, we must rely on self-report. Although the role of fMRI cannot be understated in the future.
Most researchers in the area of pain management consider the following to be important ways to determine efficacy of any intervention:
- reduced pain intensity
- reduced use of health care resources
- reduced disability including return to work, reduced need for external assistance such as home help, increased exercise level etc
- reduction of distress (often measured through reduction in health care use, improved mood etc)
- improved mood including increased social engagement
I refer 'Herb' to authors such as Turk, Rudy, Waddell, Main, Jensen et al for further information on both the management and measurement of pain.
The 'art' of health care (whether medical or allied health) relies on empiricism, whether this is from observation or RCT. My belief is that 'art' is akin to 'intuitive' and 'intuitive' is probably well-learned skills that are now automatic and not subject to cognitive analysis (The only thing to remember with observational studies is the degree of generalisation able to be derived from such studies - randomisation allows for more generalisation than individual anecdote).
'Herb' asks whether people who are **'trying to reduce their pain, suffering and anguish.*** are, in doing this, experiencing a ***reduction of pain, [which is] in some, the side-effect of some degree of “happiness.”***
Yes - but how do you or I compare our experience of pain? How do you and I determine how much suffering is 'too much'?
I can't ascertain whether the pain I experience from fibromyalgia is 'worse than' the pain I experience from 'major depressive disorder'. If I can't do that, and I am conducting an intra-subject study, how can society at large do that in an inter-subject design?!
I wonder whether ACCEPTANCE is an under-represented construct in the whole pain/mood debate.
**In “adiemus’” post he/she speaks of “serious brain surgery” which this therapy does not entail.** - Although this may not entail 'brain' surgery, it does entail planned trauma to the neurological system.
As a long-time experiencer (sorry about the grammar!) of low mood, receiving both psychotherapy and medication for low mood over the past 17 years, and as both a clinician and researcher in the area of chronic pain management (and a senior clinical lecturer of both undergrad and postgrad medical and allied health practitioners - just to flaunt my credentials!!), I think I can speak both from a personal and evidential viewpoint when I speak of the place of caution in applying invasive procedures for experiences like depression, chronic pain, and the like.
At this stage of my life, I am thankful for the influence of medication - but guarded in my confidence in invasive procedures. We know so very little about homeostasis in the CNS, in fact, we know so little about the nervous system! that it makes me feel extremely nervous both about the cost of invasive surgery and about the poor efficacy of these procedures.
People I have worked with who have chronic pain and have proceeded to things like spinal cord stimulators have universally had poor results, despite being 'excellent' candidates - somehow the nervous system sets up a homeostatic response and returns to the initial situation. The only thing that has changed pre and post surgery is:
- the 'investment' of highly invasive neurosurgery
- the increased risk of complication from the above
- the lack of future options - what is left when the last option has been carried out?
- and finally, the incredible distress experienced by the person with dashed hopes, their family with dashed hopes, their insurance providers with cynicism, their employers with cynicism and every treatment provider who then knows that this person not only is a 'nonresponder' to medication, conventional surgery, and allied therapeutics, but also to neurosurgery.
The cited '50%' of nonresponders is just that - cited, in a study that has yet to be verified using standard, evidence-based measures by uninvolved scientists.
What happens to the 50% who don't respond?
Surely as people working with people we need to continue to sincerely study what to do when interventions DON'T work.
As a patient, I plead - carry on studying how resilient people cope.
As a clinician, I plead - carry on studying how I can help people cope DESPITE treatment failure (because it happens).
As an educator and academic, I plead - carry on scientifically studying the area so I (and others) can help health care providers carefully and rationally evaluate outcome studies, not just studies for the short-term, but studies over the long-term.

Anonymous said...

The many faces of Herb Stein:

So you know who you're dealing with a little better.

Anonymous said...

Michael Schlosser, M.D., FDA clinical reviewer, began by reviewing the stimulation parameters used in the study. The study protocol limited current output to 0.25–3.5 mA, with adjustments in 0.25 mA steps until a maximum tolerable level was reached. The programming phase of the study’s acute phase lasted two weeks, during which programmers could adjust a participant’s current level. The sponsor sent a letter to the pivotal D-02 study investigators in April 2002 outlining a new stimulation protocol used for nonresponders.

Dr. Schlosser first covered the safety data for the pilot D-01 study, in which every subject reported at least one adverse event. Greater than 50% of the patients reported serious adverse events, including 12 suicide attempts, 34 cases of worsening depression, and one death during a surgery for rectal prolapse.

In the pivotal D-02 acute phase, nearly every patient reported an adverse event; severe adverse events were reported among 61 subjects in the treatment control group (including one suicide) and 73 in the sham group. In the long-term phase of the pivotal D-02 study, there were seven suicide attempts. Dr. Schlosser remarked that the sponsor believes that the 62 episodes of depression among 31 subjects in the long-term phase to be due to a lack of efficacy of the device than a true serious adverse effect. Safety data was not collected for the observational, control D-04 study.

The European D-03 study, an open label, non-randomized, single-arm study, is still underway. The 47 subjects receiving implantation of the VNS device reported 14 serious adverse events, including two suicides. Dr. Schlosser also briefly presented the Sponsor-Investigator D-06 study, an open label, non-randomized, study with a single treatment arm that looked at VNS therapy for patients with rapid cycling bipolar disorder. One suicide and two suicide attempts were reported in the seven implanted patients.

Dr. Schlosser noted that the FDA is concerned about the number of suicide attempts among the participants in these studies. He reminded panel members that the safety analysis of a device is done as a risk-benefit equation; therefore, the safety in the epilepsy population does not equate safety in the TRD population.

But Dr. Michael Thase, a psychiatrist at the University of Pittsburgh who consults for the company, said there was "simply not a good enough basis in evidence" for approval. While the device is promising, Dr. Thase said, "the shaky state of the evidence means we have to be very cautious with this and prepare for the possibility that the hoped-for benefit isn't there."

But the panel did not hear from patients who did not benefit from the stimulator, according to the transcripts. One of them, Katherine Coram, 57, of Silver Spring, Md., signed up for the trial after seeing a newspaper advertisement about it.

"Believe me, when you're depressed for long enough, you get to a stage where you're willing to try almost anything," Ms. Coram said in an interview.

In the study, doctors implanted the device in 235 severely depressed people. The stimulator sends timed pulses of electricity to the vagus nerve, which has wide connections throughout the brain.

Half of the patients then had their stimulators turned on. The investigators did not know which of their patients had their stimulators on.

After three months, researchers "unblinded" the study and compared levels of depression in the two groups based on standard measures of disease severity, the F.D.A. documents show. They found that 17 of the 111 patients who had implants turned on and completed the trial showed significant improvement. But 11 of 110 who had no stimulation and completed the trial also felt significantly better. The difference between the two groups was small enough to be attributable to chance.

Alan Totah, vice president of regulatory affairs for Cyberonics, said at the meeting, "The primary endpoint did not reach statistical significance." But Mr. Totah said "the results did show a positive trend in favor" of the stimulator.

Hoarseness was a common complaint. Many patients who have had a stimulator on also said that it put a quiver, rumble or other odd inflection in their voices.

"I certainly knew mine was on," Ms. Coram said. "I could feel it. You get this constricting pain in the back of the throat. I couldn't talk sometimes."

Ms. Coram said that she was slightly more functional at work after the surgery but that it did not last. Later, she said, after she took a doctor's advice and had the stimulator's pulse turned up higher, "my life fell apart."

"I was very anxious and agitated, much more so than before," she went on. "I felt suicidal for a while, worse than I had been in 8 to 10 years."

But several members of the panel that voted for approval said that given the alternatives for people like Mr. Donovan and others who did well, the insignificant difference between the two groups was cast in a different light.

"The feeling was that anything that gives these people hope is potentially worthwhile," the chairwoman, Dr. Kyra Becker, a neurologist at the University of Washington, said in an interview. "But the whole meeting was uncomfortable, and everyone wanted to see another trial done, no question about it."

Dr. Becker said that if she had voted her conscience, solely on the basis of the evidence, she would have voted not to approve.

A member who voted against approval, Dr. Richard Malone, a psychiatrist at Drexel University College of Medicine in Philadelphia, said he was bewildered by the recommendation.

"I walked out of there thinking I was nuts," Dr. Malone said in an interview. "It was stunning, but then I find much of life is stunning."

Others have had far less positive experiences. Among them is Katherine V. Coram, 58, of Silver Spring who got the implant in the same study as Donovan. Coram said she knew she was in the group with the activated device because she could feel it going off, she said. She frequently lost her voice while she was talking and felt a persistent constriction in the back of her throat. Both are common side effects of VNS treatment.

Coram said the device seemed to help a bit at first, but when the doctor turned up the settings, she felt suicidal for the first time in years. Worsening depression and suicide attempts were reported by one-third of patients in one study funded by Cyberonics, according to data presented to the FDA.

Last year Coram said she had the generator removed from her chest because it wasn't helping. The electrodes in her neck must remain forever; doctors tell VNS patients that removing them is too risky because tissue grows around them As a result, VNS recipients cannot undergo a full body MRI or therapeutic ultrasound.

"I'm still angry about the whole thing," said Coram, who said she regrets getting the implant and currently relies on the standby treatments: psychotherapy and antidepressants.

"You get desperate when you've been depressed for years," she said. "This sounds benign, like a pacemaker. My crusade is for people to know a lot more about it before they sign up." ·

Houston Press 2005-04-07

Exposed Nerve

And Cyberonics has an interesting history with the FDA.

In 2001, the agency issued a warning letter to the company for failing to properly report 60 deaths its pacemaker could have caused or contributed to. The company also failed to properly report 102 patient infections. Cyberonics had withheld the data from the FDA until two months after a routine inspection.

Cyberonics resolved those issues but received another warning letter last December, which the company must rectify for full approval.

Cyberonics is optimistic the FDA will give it the key to the depression market. In a press release, the company described the federal violations outlined in the warning letter as "outstanding bioresearch monitoring issues," which is the company's way of telling shareholders it must do the following:

1. Investigate and explain why thousands of patients had to be reimplanted with a second pacemaker;

2. Investigate and explain the causes of 81 deaths reported between 2001 and 2003; and

3. Investigate and explain the cause of each reported adverse effect, including instances where the device dislodged and migrated throughout the body; cases of vocal cord paralysis; and increased seizures.

Cyberonics' patient's manual lists a total of nine side effects, including skin irritation, blood clotting, paralysis of nearby nerves and muscles, and changes in heart rate. The physician's manual lists 49 side effects, including device migration, insomnia, gastric ulcers and formation of fibrous tissue. And, unlike the patient's manual, the physician's manual explains that the electrical leads can in fact paralyze the nerve they're supposed to stimulate.

But Suzanne Parisian, who briefly served as the FDA's chief medical device officer in the mid-'90s, says the warning letters should be taken seriously.

"You have [60] people with epilepsy that had this implanted device that the FDA was never told that they died, and the company never did an investigation as to why they died, and the company's contending that the device is safe and effective," she says. "It's very unlikely that anybody will do any kind of an examination in these patients to find out why they're dying, and then you're asking them to expand the indication to depression patients."

Moreover, she says, the FDA is set up to put products on the market, not to play detective. Reviewers are dependent on manufacturer reports; officers base their decisions on paperwork -- they never see the actual devices. The agency also depends in large part on pharmaceutical and medical device companies' funding. Drug companies have paid steep "user fees" since 1992; medical device companies since 2002. In exchange, the FDA promises to expedite the decision-making process. It's supposed to buy efficiency, not approval, but Parisian calls it quid pro quo.

The FDA reported that the company relied on nonrandomized clinical studies with a potential bias. The agency also expressed concern over instances of study patients whose depression deepened, and the fact that there was no statistical difference between a group of patients who had the device turned on and a control group whose devices were off.

Richard Malone, a psychiatrist and professor of psychiatry at Drexel College of Medicine in Philadelphia, was one of two advisory panel members to vote against recommending the treatment for depression.

"For the VNS, there was no evidence that the real treatment was better than the fake treatment," Malone says. "So then…you have a treatment that doesn't have evidence of working but does have evidence of side effects."

John Rush, a distinguished psychiatrist with the University of Texas-Southwestern Medical College, designed the clinical depression study. He told the panel in June that, at the time of the study, conducting a yearlong controlled study would have compromised patient safety.

"We didn't know if they would get better [or if] they would get worse," Rush told the panel, according to transcripts. "We didn't know how many would kill themselves. We had no idea. No one has ever reported this…So we were wrestling with a -- really a totally new territory, a terribly difficult illness with a very high risk of disability [or] death. You saw a hospitalization, we had a patient suicide who was a physician and so on."

But Malone disagrees.

"They claimed that they couldn't do more studies because it wouldn't be ethical," he says. "But I just replied that it's in the same way not an ethical thing to recommend treatment."

Although the FDA initially rejected the panel's approval recommendation, it reversed its decision in February after the company submitted supplements to the original study.

With their depression therapy deemed "approvable," Cyberonics' stock jumped 42 percent the day after the announcement. Cummins told shareholders the company would enter the depression market in May, and he technically didn't have to tell them anything at all.

The FDA does not disclose approvable letters, deferring instead to the manufacturer. A company can choose not to reveal the terms of approvable letters to the public and to shareholders, meaning the disclosure of potential public health concerns is up to corporations, whose sole legal purpose is to generate profit.

Shortly after the approvable letter, Cummins sold stock for the first time, puzzling some shareholders. However, he explained to investors that the 350,000 shares he sold was less than a quarter of his holdings.

"I did what I had to do to reduce my family's exposure and risks, knowing that the 1.15 million options I still hold will be more than enough when this company's enormous potential and value are recognized in the next two years," Cummins explained in a letter.

The FDA warning letter demanding reasons for unexplained deaths and thousands of explanted devices never had any effect on stock. As long as a product is on the market, and as long as no one talks about warning letters, a company will continue making money.

No one likes talking about warning letters, and no one likes talking about unproven therapy.

FDA medical device director Dan Schultze declined to be interviewed, referring questions to a spokesperson who stopped answering them after a while.

Cyberonics board member Stanley Appel, chairman of the neurology department at Baylor College of Medicine, also refused comment.

Spokespeople for the Houston and national chapters of the National Alliance for the Mentally Ill and the Depression and Bipolar Support Alliance, as well as the Mental Health Association of Greater Houston, said they did not offer opinions on therapy.

Yet Lydia Lewis, president of the Chicago-based DBSA -- a nonprofit that receives financial support from Cyberonics and pharmaceutical companies -- appeared before the advisory panel last June, advocating for more treatment options. Lewis chose her words carefully, lest she be accused of endorsing Cyberonics.

"I am not here to advocate for any particular therapy, including VNS, but rather for the critical need for new therapies," she told the panel, according to transcripts. "At DBSA, we know that new drugs and non-pharmacologic treatments are desperately needed. Far too many people are dying or living lives of quiet desperation, because they can't get sufficient relief from their symptoms of depression. The more treatments the FDA makes available, the more lives that will be saved."

Even outspoken FDA watchdog Public Citizen, a group that has weighed in extensively on the recent controversy over Vioxx, Celebrex and Bextra, said it has no staff members familiar with vagal therapy.

Fortunately, there are online forums where current or prospective Cyberonics patients can share information. Up until February 2004, Cyberonics had its own forum. But the company shut it down, explaining that "Increasingly…the message board has been an instrument for abuse by certain individuals."

According to former forum members, the shutdown came on the heels of a patient posting a link to the FDA's database of product problems. The database lists 500 adverse events for Cyberonics between May and December 2004 and 1,414 for 2002. Data for 2003 is not available online. Events range from increased seizures to death, which is often described as "sudden unexplained death in epilepsy." In many cases, Cyberonics reported that surgeons refused to provide in-depth information so the company could find the cause of the problem. In one case of an inverted device, a neurologist "asked that he not be contacted regarding the event, as he has a limited staff and is subsequently not able to respond to mfr's request for additional info."

Cyberonics received a similar cold shoulder regarding a patient who died five days after implantation. In the case of one patient who developed a wheezing problem, the company could not investigate because whoever reported the problem forgot the patient's name. Some of the cases in which Cyberonics could figure out what went wrong are troubling as well, including the instance of a surgeon who implanted the device when it was already on. The device is not supposed to be activated until two weeks after surgery.

A week after Cyberonics removed its forum, former VNS patient Donna Baum launched what has become one of the Web's most popular alternatives. Baum, 50, had her pacemaker turned off after she experienced constant pain in her arm. She says the device reduced her seizures, and cut her postseizure recovery period from days to hours. But she also suffered breathlessness and nights where she'd wake up with vomit in her lungs. She says the device also eliminated her auras, which are signals some epileptics get of oncoming seizures.

Baum had her surgery before 2001, the year that Cyberonics placed its patient's manual online. Like many others on her forum, she didn't know a patient's manual existed until she was handed one after surgery. She says she wants her forum to be a place where current and prospective patients can get the kind of information she never got.

"I've never said the device is bad," she says from her home in Las Vegas. "I never said it needs to be pulled off the market. What I stated is 'research, research, research.' You need to know more than your doctor."

Naïveté and desperation play too big a role in prospective patients' decisions, she says.

In the case of Cyberonics' approvable letter, "It's being done, No. 1, on the company's guarantee that they're going to be good boys because they're going to tell FDA everything," she says. "And yet we have a company with a history, that hasn't been telling FDA everything. So it doesn't really make sense, does it?"

A potent, fast-acting, safe, side-effect-free antidepressant treatment still eludes researchers and physicians. That it has not been forthcoming may have something to do with how little is understood about what's behind this illness and the variety of forms it may take. Genetics is certainly at play, as is early childhood trauma and later stressors. Loss of a loved one can bring it about. On the other hand, some people exposed to the most horrendous circumstances never experience a whiff of depression.

Different therapies, including VNS, rTMS, and DBS, may work for different subsets of patients and phases of the illness. Even the long-abandoned anger-turned-inward business may have its place. After all, despite all the antidepressants being handed around, victims of depression continue to murder themselves at a rate about 70 times that of the general population. Maybe Freud was on to something.

Anonymous said...

Dear Doc (adiemus),

I apologize for my tardiness in responding to your posting but quite frankly I have been extremely busy in my mental health advocacy and pro-activism and although I quickly read your information I have not had the time to investigate your suggested reading sources in order to properly respond.

As you may have also noted I’ve accumulated a number of closet misfits and deviants who have followed my advocacy through the years from venue to venue sharing their pubescent intellect.

I’d like to take a quick moment to share a recent advocacy E-mail of mine.

Subject: VNS Therapy for TRD (Cyberonics) - Neurological Devices Panel of the Medical Devices Advisory Committee meeting to be held on January 26, 2007

When possible and time afford me, I would then like to address your comments after reading your suggested source materials.

I thank you and the other knowledgeable and respectful participants for sharing your thoughts with me. It is appreciated.



Alcibiades said...

It depends what you are treating. VNS was used for treating -epilepsy- and happened to have a noticeable beneficial side effect of antidepression.
That's the spin: it's not an antidepressant, it's an antiseizure treatment. To give VNS surgery for depression isn't really what it's for -- nor what it's been tested for. I have VNS; but it's for -- epilepsy :D