Source: New York Times
Date: 6 September 2006

Battle Lines in Treating Depression


TAMARA KNIGHT remembers little of the summer of 2004 beyond a numbing despair that resisted 16 different antidepressant drugs. She dreaded a return to electroshock therapy, which she had tried periodically for years, because it brightened her mood for only a few weeks, at best, while progressively destroying her memory.

“She was in as dark and low a place as you can ever imagine a person living,” said Don Knight, her husband. So Ms. Knight drove to a drugstore in her hometown of Columbus, Ga., bought two large bottles of extra-strength Excedrin and two boxes of sleeping pills. She said she swallowed as many of the pills as she could before she passed out.

Katherine V. Coram, another depression sufferer with a history of attempted suicide, was in relatively better shape that same summer. She had managed to cling to a job at the National Archives in Washington, where an understanding boss gave her a light workload. But Ms. Coram felt defeated. Her three years in a clinical trial to see if an implanted nerve stimulator could control her illness had ended with hellish results.

“I was hospitalized three times in the year after I got it for anxiety, panic and other problems — after having gone 15 years without hospitalization,” said Ms. Coram, who lives alone in Silver Spring, Md. “Once I even hit a stranger in a restaurant after I got mad. It was totally out of character for me.”

The summer of 2004 was also trying for Cyberonics, a small Houston company that made Ms. Coram’s stimulator, and Robert P. Cummins, known as Skip, the company’s combative chief executive. A Food and Drug Administration panel recommended in June that the agency approve the device — a pocket-watch-sized generator implanted in the chest that transmits electronic pulses to a major nerve pathway in the neck — for treating the most intractable forms of depression. But about two months later, the F.D.A. ignored its own panel’s recommendation and decided to withhold approval after weighing criticisms from groups opposed to the controversial treatment.

Since 2004, Ms. Knight and Ms. Coram have continued their struggles with depression, their fates intersecting with Cyberonics’ own battles with the F.D.A. and insurers, as well as medical skeptics and public interest groups who argue that the company is peddling false hopes built on a still unproved technology.

The struggle over the future of the $15,000 device, which costs another $10,000 or more to implant, is being played out against that most tender of landscapes: the human psyche and the unpredictable and poorly mapped fault lines that cause depression and separate people from themselves and the world around them.

IT is a very promising avenue of research, and the long-term data they are pushing are encouraging,” said Dr. Christopher Gorton, chief medical officer of APS Healthcare, a consulting firm that was hired by the state of South Carolina to review Cyberonics’ research results. “But people have a legitimate need to be cautious. Even the sponsors admit they don’t know exactly how it works. The psychiatric literature is full of people clutching at straws.”

Some 21 million American adults suffer from depression, according to the National Institute of Mental Health, a federal research agency. While doctors as far back as the Renaissance speculated that mood disorders had medical roots, it was not until the end of the 19th century that such views were widely accepted. Since then, mental health care has seen innovations in talk therapy, electroshock, surgical procedures, drugs and, most recently, implanted devices.

Along the way, there have been notorious examples of misplaced medical enthusiasm, including adoption of lobotomies to treat depression. Currently, critics complain about frequent misuse of electroshock therapy and the virtually unregulated mixing of potent antidepression and antipsychotic drugs.

Cyberonics, which finally secured F.D.A. approval to market its implant last year, has ventured into the most difficult corner of depression treatment. It says its stimulator can provide relief for many of the four million or so people who suffer from “treatment resistant depression,” or T.R.D., a form so severe that patients fail to respond to drugs and traditional shock therapy. No other product has ever been designed for — and tested exclusively on — such a severely depressed population.

During the last month, some 1,300 doctors, patients and Cyberonics employees have written to the Centers for Medicare and Medicaid Services, asking that the agency grant Cyberonics’ recent petition for Medicare coverage. Public Citizen, a consumer advocacy group in Washington, filed a competing request on Wednesday, asking the agency to deny coverage. The group contends that Cyberonics has relied on misleading advertising and clinical trial write-ups, among other tactics, to secure federal approvals.

“With substantial constraints on the Medicare budget and so many clear needs going unmet, it seems absurd to flush away millions of dollars on this unproven device,” wrote Dr. Peter Lurie, deputy director of health research for Public Citizen, in the group’s petition. Other problems loom over the company. Federal prosecutors and regulators are investigating its pay practices, according to recent securities filings. Earnings disappointments over the last year have also caused Cyberonics’ stock to drop to $17.30 from a 52-week high of $40.69. Mr. Cummins declined to comment on the investigations, which are continuing.

But in an e-mail message last week, he scornfully dismissed Public Citizen’s criticisms as “shrill” and questioned Dr. Lurie’s expertise. “I look forward to the day when T.R.D. patients and fully qualified psychiatrists have the right to make treatment decisions regarding the ONLY treatment ever studied, proven safe and effective and F.D.A. approved for the long-term treatment of T.R.D!” he wrote.

The Cyberonics implant, like so many modern medical devices born of recent technological advances, would have been unimaginable only a generation ago. After being implanted in a patient’s chest, the device is surgically wired to the neck’s left vagus nerve, a major pathway for nerve signals to the brain from the heart and torso. Research suggests that repeated electronic stimulation of the vagus nerve can help treat severe depression by altering chemical and electrical functions in areas of the brain linked to mood disorders.

Cyberonics, which was founded in 1987, initially developed the stimulator to help epileptics control seizures. The F.D.A. approved that use in 1997. In 1998, based on animal tests and reports that many epileptics with the implant experienced mood improvements, Mr. Cummins gambled Cyberonics’ future on the idea that the device could also help treat patients with T.R.D. — people like Ms. Knight and Ms. Coram.

Mr. Cummins forecast, to Wall Street’s delight, that the T.R.D. market might be 10 times bigger than the epilepsy market. But his zeal also reflected his own family’s experience with depression, an affliction he says drove his mother and his grandfather to suicide. “My mother was my object lesson in wasted potential,” he said.

A squarely built, 6-foot-2-inch former college linebacker, Mr. Cummins, 52, says his mantra is, “Maybe wrong but never in doubt.” His shaved head and nonstop intensity seem well suited to someone whose idea of relaxation is competing in Nascar-affiliated car racing events. He now owns a Daytona Prototype race car — named Cyberspeed in honor of his company.

A native of Grove City, Pa., Mr. Cummins is the youngest of three children born into a dysfunctional family that he said was ripped apart by the periodic absences of his father, a steelworker, and his mother’s depression, alcohol and drug addictions. A decent student and a star athlete, he won a scholarship to Dartmouth, where he majored in government affairs.

After earning an M.B.A. at the University of Illinois at Urbana-Champaign Mr. Cummins eventually became a venture capitalist, joining Cyberonics’ board in 1988. Cyberonics was the brainchild of Reese S. Terry Jr., a veteran of the medical device industry, who set up the company to develop nerve-stimulation technology invented by Dr. Jacob Zabara at Temple University.

Dr. Zabara was one of many researchers exploring how electrical stimulation of the nervous system and the brain could affect a range of mental and physical ailments. The neurostimulation market as a whole now generates $1 billion annually in revenue, according to Wall Street analysts, and includes devices like spinal-cord stimulators that mask pain and deep brain implants that control some symptoms of Parkinson’s disease.

Wall Street and leading device companies see neurostimulation growing into a $10 billion business in the next decade, thanks to rapid advances in microchips and sensors. Executives at Cyberonics say that focusing on the vagus nerve makes its implants as effective but less risky and invasive than those that stimulate the brain and spinal cord.

Mr. Cummins became Cyberonics’ chief executive in 1995, when the company was struggling to stay afloat financially while seeking regulatory approval of its epilepsy therapy. He took over about the same time that Tamara Knight began a seemingly irreversible slide into severe depression.

Ms. Knight began suffering from depression as a teenager, a struggle that led to an early suicide attempt. Several years ago, drugs that had helped her recover stopped working. She began to neglect housework and her three children. In the fall of 1998, after several incidents in which she became outraged with co-workers, she lost her job. That winter, she began electroshock therapy.

What followed, she said, were more than 30 such treatments and more hospitalizations than she can recall. The number of drugs she took kept increasing, along with her weight. At one point, Ms. Knight, who is 5-foot-6 and had struggled with anorexia as a teenager, weighed more than 200 pounds. By 2004, she was depressed and was suffering from a common side effect of the electroshock therapy required to control her suicidal impulses: a steady erosion of her memory.

“Moneywise, insurance and Medicare paid for them,” Ms. Knight said of her treatments. “But it cost 30 years of my life in memory loss.”

As often happens in cases of severe depression, the family says it also lost the support of outsiders, including its local church. “If Tamara had had cancer, our church would have had people visiting all the time,” Mr. Knight said. “One older man visited us as long as he was able. That was it. It was a real blow to our faith.”

When Ms. Knight’s psychiatrist recommended a Cyberonics implant shortly after the F.D.A. approved the device in 2005, she became enthusiastic. Mr. Knight, who said he thought that V.N.S. therapy — Cyberonics’ trademarked name for “vagus nerve stimulation” — sounded far-fetched when he heard about it a few years earlier, now agreed that it was a chance they had to take.

HE was worried, though, that public information about V.N.S. came largely from Cyberonics and highlighted favorable aspects of clinical data. Negative experiences of clinical-study patients like Katherine Coram were not readily available, outside of commentaries that epilepsy patients posted on a Cyberonics Web site.

Ms. Coram recalls feeling better in the first six months after her Cyberonics stimulator first turned on in 2001.

But when researchers ramped up her implant’s power to enhance its long-term performance, Ms. Coram began suffering nausea, sleeplessness and panic attacks that sent her to the hospital. She lost track of her finances. Like many victims of severe depression, she also began to experience distressingly peculiar setbacks, including an inability to load her dishwasher. Ms. Coram said doctors raised and lowered the implant’s power level several times before she asked them to turn it off temporarily.

“I was trusting the people in the study to figure out how to use the device but they didn’t have a clue,” Ms. Coram said.

The experiences of individuals like Ms. Coram and inconclusive data were not enough, though, for the F.D.A. to shut its doors to Cyberonics. In June 2004, an advisory panel recommended that the agency allow Cyberonics to market its stimulator.

That same night, Cyberonics’ board granted Mr. Cummins a bonus of 150,000 stock options. The next day, as the stock market reacted to the F.D.A. panel’s recommendation, Cyberonics shares leapt 77 percent, laying the groundwork for what, two years later, would become inquiries by the Securities and Exchange Commission and the Justice Department into whether Mr. Cummins’s options grant was legal.

But in 2004, Mr. Cummins had more immediate problems. By early August, critics inside and outside the F.D.A. had talked the agency into the unusual step of disagreeing with its advisory panel. True, there were success stories from patients who achieved almost complete recoveries (nearly 20 percent, according to Cyberonics). Data also suggested that patients who benefited — over 50 percent to one degree or another — were more likely to avoid relapses, expensive hospitalizations and suicide than a similar group of patients who received conventional therapy.

Still, in the most carefully controlled trial, a group that had the device implanted but not turned on fared nearly as well as the group being stimulated. Critics also pointed out that long-term results indicated that 30 percent of the patients reported worsening depression similar to Ms. Coram’s, creating unanswered questions about potential harm.

Mr. Cummins said in a press release that Cyberonics was “shocked” by the agency’s rejection. He denigrated the F.D.A. request for more randomized testing, arguing that other antidepression therapies had been subjected to far less challenging scrutiny. And he suggested to analysts that the agency’s decision would leave many patients feeling that they had no option other than suicide. In September, the F.D.A. accepted an amended application from Cyberonics that contained more long-term performance data and comparisons to other therapies.

Still, it came as something of a surprise on Wall Street and in the medical device industry when the F.D.A. decided early in February 2005 to approve V.N.S. as a depression treatment if Cyberonics met certain conditions. Most of the new requirements dealt with follow-up studies aimed at figuring out how the device could be used most effectively. Mr. Cummins forecast that all of the conditions could be met by the end of May. Shares of Cyberonics soared, and the company went on a hiring spree.

Mr. Cummins cast the decision as a victory for patients but also heralded the financial upside, projecting that Cyberonics’ sales could reach $1 billion by 2010. In the weeks after the F.D.A.’s announcement, he responded to Cyberonics’ stock run-up by exercising options on 350,000 shares, which netted him about $10.75 million. (The sales left him holding just over 36,000 Cyberonics shares, a stake he has since raised to 173,750 shares, according to federal filings.)

The long-awaited marketing approval from the F.D.A. came in July, but new problems emerged. A prominent board member resigned, citing disagreements with other directors over compensation policies and lack of a succession plan for Mr. Cummins.

The Senate Finance Committee, which began investigating the F.D.A.’s handling of the implant that spring, issued a staffreport in February of this year criticizing Dr. Daniel G. Schultz, a senior F.D.A. official, for overruling agency experts opposed to the device. An F.D.A. spokeswoman said that the agency acted carefully and that for “the small number of patients with severe depression who have failed all other treatments, data shows this may be the difference between being able to live a more productive life or suffer from debilitating illness.”

The Senate report also put Medicare officials on notice that decisions to cover V.N.S. would invite further scrutiny.

Continued uncertainty surrounding V.N.S. and Mr. Cummins’s us-against-the-world attitude have taken their toll on Cyberonics’ stock price and on Wall Street’s faith in the company. “There are institutional investors who won’t touch the company as long as Skip is at the helm,” said Jan Wald, an analyst at A. G. Edwards & Sons.

To hear Mr. Cummins tell it, what really matters is that a growing number of depression patients now credit the device with saving their lives. They include Ms. Knight, who got her Cyberonics implant last October, and quickly proved to be the kind of patient the company treasures.

“My family could see subtle differences right away,” Ms. Knight recalled in the letter of support for V.N.S. she sent to Medicare regulators last month. “I was out of bed more often and started taking an interest in how the house looked.”

While Ms. Knight, now 47, talks about “having my life back,” the legacy of severe depression remains with her. After spending so much time for so many years in bed, her body cannot keep up with all the things she now wants to do around the house, often leaving her in pain. She continues to lose her way around her hometown and mourns the loss of so much of her long-term memory. But she has been able to cut back to using just three medications, a change she credits with helping her shed 40 pounds.

MS. CORAM is also on the mend, but not because of V.N.S. or Cyberonics. After enduring numerous futile adjustments to her implant and having it temporarily turned off, she asked her doctors to try one last time in March 2004. Three months later, she stopped using the implant for good and then had it removed from her chest. Her doctors left the metal leads wrapped around her vagus nerve, saying it was too risky to try to remove them.

She said she is slowly regaining the ability to do household tasks — like paying bills — that had been impossible during her V.N.S. treatment. “I feel like I’m just beginning to get my life back,” she said recently.

Mr. Cummins remains as driven as ever. Cyberonics says 1,810 patients have received the implants since the product was approved, out of 13,313 identified candidates. Thousands have been caught up in lengthy and often unsuccessful appeals for insurance coverage, since only a few small insurers routinely pay for the device.

Seeking the traction it desperately needs with insurers, Cyberonics decided in May to narrow the company’s focus to the subset of T.R.D. patients whose problems are the most costly for health care providers. Cyberonics contends that V.N.S. treatment for that group would save hospitals $4,800 to $8,200 a patient annually, based on an estimate of the implant’s cost and follow-up visits over eight years. But Cyberonics’ calculation is based on optimistic presumptions, including aggressive estimates about the pace and nature of patients’ recovery.

Because the presumptions are also based primarily on results from earlier trials, critics like Public Citizen say the new focus has all the flaws of the old one.

However the controversy is resolved, depression victims who finally get an implant will find themselves entering a medical lottery. Many, like Joe Marhefka, 49, of Colchester, Conn., are too depressed to be optimistic about the procedure.

Mr. Marhefka, who ended up in the hospital last fall after attempting suicide, said that he masked his depression most of his life by drinking. When he gave up alcohol eight years ago, the depression seemed to intensify. He said electroshock therapy two years ago destroyed most of his memories of his adolescence, and younger adult years. He lost his job as a high school math teacher shortly before his suicide attempt.

“When I had the implant last month, I was hoping I wouldn’t wake up,” Mr. Marhefka said in July, before entering the New London, Conn., office of Dr. Kathleen R. Degen to have his stimulator activated. “I don’t have any hopes this is going to work. I’m doing this because my wife deserves a husband and my two daughters deserve a Dad. They have hope. I’m just going along with the doctors.”

Dr. Degen used a hand-held computer to program a wand that Mr. Marhefka held over the spot on his chest where his implant was located. A 30-second-long pulse surged into his vagus nerve, reducing Mr. Marhefka’s voice to a barely audible rasp. When the pulse stopped, his voice returned to normal and he conversed briefly with Dr. Degen. He asked about reducing his medications; Dr. Degen said the request was common, but that it was too early to consider it.

Five minutes later, just as Mr. Marhefka asked whether his implant was still on, it delivered its second pulse — again taking away his voice and leaving him with what he said was a mild strangling feeling. Dr. Degen let the pulse pass and explained how she would gauge his future progress.

But Mr. Marhefka plans to measure his progress with his own yardstick.

“If I start smiling again, maybe even laughing sometimes, that’s how I’ll know,” he had said just before entering Dr. Degen’s office. So far, Mr. Marhefka said in a phone call last week, he is still waiting.

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