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F.D.A. Considers Implant Device for Depression
by BENEDICT CAREY, New York Times, 21 May 2005

The Food and Drug Administration may soon approve a medical device that would be the first new treatment option for severely depressed patients in a generation, despite the misgivings of many experts who say there is little evidence that it works.

The pacemaker-like device, called a vagus nerve stimulator, is surgically implanted in the upper chest, and its wires are threaded into the neck, where it stimulates a nerve leading to the brain. It has been approved since 1997 for the treatment of some epilepsy patients, and the drug agency has told the manufacturer that it is now "approvable" for severe depression that is resistant to other treatment.

But in the only rigorously controlled trial so far in depressed patients, the stimulator was no more effective than surgery in which it was implanted but not turned on.

While some patients show significantly improved moods after having the $15,000 device implanted, most do not, the study found. And once the device is implanted, it is hard to remove entirely; surgeons say the wire leads are usually left inside the neck.

Proponents say that many severely depressed patients do not respond to antidepressants or electroshock therapy and that those patients are desperate for any treatment to relieve their suffering.

"These people have no other options, so we need to consider anything that shows potential to help," said Dr. Harold A. Sackeim, chief of biological psychiatry at the New York State Psychiatric Institute, who consults for Cyberonics Inc., the Houston company that makes the stimulator.

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."

The drug agency has given mixed signals about the stimulator. In August 2004, it told Cyberonics in a letter that the treatment was not approvable, saying more information was needed. But in February, after the company provided more data, the agency changed that position, informing the company that the stimulator could now be approved. The company's stock price has fluctuated as investors try to anticipate the agency's decision, which the company is hopeful will come by the end of the month.

The Senate Finance Committee recently began looking into the F.D.A.'s potential reversal, but Cyberonics officials say they have been assured by the agency that this will have no bearing on its final decision.

In a conference call with reporters and analysts on Thursday, Robert Cummins, the company's chief executive, said no other treatment had been deemed approvable by the drug agency for stubbornly depressed patients. Clearly, he said, "the status quo for millions of Americans, their families, psychiatrists and payers is neither safe nor effective."

Still, some patient advocates and other experts are now questioning how the device has come so close to approval with such limited evidence for its effectiveness.

"I've never seen anything quite like this," said Dr. Peter Lurie, deputy director of health research at Public Citizen, a nonprofit group that is a frequent critic of the F.D.A. and the drug and medical-device industries. "What we could be setting ourselves up for is an epidemic of implantation of a device with no proven effectiveness."

Experts who were involved in the approval process say they were moved by the desperate prognosis for severe depression and by powerful testimonials.

At a critical meeting of an F.D.A. panel last June, six patients with chronic severe depression said they felt much better that the stimulator had been implanted, as part of an investigational study. At that meeting, the panel voted 5 to 2 to recommend that the device be approved.

One patient, Charles Donovan III of St. Louis, said the stimulator had saved his life. "I went from being a complete mental-health vegetable to someone who had the energy and confidence to do this book," Mr. Donovan said in an interview.

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."

The F.D.A. usually follows the recommendations of advisory panels.

Another reason some psychiatrists are intrigued by the device for depression is a finding in the evidence that some people with the implant might do better over time. In follow-up data, Cyberonics reported to the drug agency that about 30 percent of those in the study showed significant improvement on one measure of depression after six months or more.

"The effect appears to be sustained, which is very significant in these patients, who almost always relapse," Dr. Sackeim said.

But other experts say it is extremely difficult to interpret this long-term evidence. Many patients in the study were taking psychiatric medications, or had electroconvulsive therapy, both of which can improve mood. These and other factors are difficult to control for, despite the company's efforts to do so, they said.

Cyberonics says that the long-term evidence it has provided to the federal agency satisfies requirements for approval, and that senior agency officials have told the company as much.

The agency has a higher standard of proof for approving new drugs than it does for devices. Devices require a "reasonable assurance" that they are safe and effective and that potential benefit outweighs the risk.

F.D.A. officials said they could not comment on any product that was pending approval. But Dr. Donna-Bea Tillman, director of the agency's office of device evaluation, said "it is not the kiss of death" if a product's effectiveness is not supported by a well-controlled clinical trial.

"We consider safety and effectiveness in relation to the alternatives that patient population has, including whether they have any alternatives at all," Dr. Tillman said.

If a device is approved, the agency specifies precisely which patients should have access to it, she said. Whether to recommend it is then left to doctors' judgment.

And that is a prime concern among critics of the approval process, like Public Citizen and other groups concerned about patient protection. Once a product has been approved, the manufacturer can promote it aggressively, and some doctors may recommend it to any patient, whether severely or moderately depressed.

Some people may not wait for approval. Sue Wanemaker, 51, who lives near Denver, said she had a vagus stimulator implanted last April for her depression. Ms. Wanemaker, who also has epilepsy, said she had noticed little benefit, and added that when turned up high the stimulation made her feel suicidal.

She has since had the device turned down. "I'm going to hang in there," she said in a phone interview, "because why not, I've got it in now, and - there it goes!" With that, her voice trilled for a few moments.

Psychiatric News May 20, 2005
Volume 40 Number 10
© 2005 American Psychiatric Association
p. 41
Clinical & Research News
Antipsychotic Use Patterns Surprise Researchers
by Mark Moran

Risperidone was the most commonly used antipsychotic drug among both boys and girls. But why these drugs are being prescribed for youngsters and who is doing the prescribing are not known.

Nearly one-fourth of patients in a commercially insured population for whom claims for atypical antipsychotic drugs were submitted were aged 9 or younger, and most of these were boys.

Those were among the findings from a period prevalence study of atypical antipsychotic drug use among commercially insured youths in the United States. The report appears in the April Archives of Pediatric Adolescent Medicine.

"We knew from previous studies that use of these drugs was increasing in children in general, but we hadn't been aware of the spike in use among boys, especially boys aged 9 and younger," lead author Lesley H. Curtis, Ph.D., told Psychiatric News. "That really surprised us."

She is an assistant research professor at Duke Clinical Research Institute in Durham, N.C.

Curtis and colleagues examined outpatient prescription claims for atypical antipsychotic drugs for 2001 from the database of a large pharmaceutical benefit manager servicing more than 6 million outpatients.

They found that the prevalence of atypical antipsychotic use was 267.1 per 100,000 subjects aged 19 years and younger. Moreover, the rate for male patients was more than double that for female patients even though male and female patients were equally represented in the overall population.

Prevalence was highest at 594.3 per 100,000 subjects among boys aged 10 to 14. Among girls the prevalence peaked at 291 per 100,000 subjects aged 15 to 19.

Most startling was the finding that nearly one-fourth of patients with a claim for atypical antipsychotic drugs were aged 9 or younger, and that 80 percent of these were boys, according to the report.

Curtis told Psychiatric News that risperidone was the most commonly used drug among both boys and girls, with olanzapine ranking second.

The conditions for which the children are being prescribed these drugs and who is doing the prescribing have yet to be determined.

"Schizophrenia is seldom diagnosed before the teenage years, so our hunch is that these drugs are being prescribed for behavioral disorders, which are known to be more common in boys," Curtis told Psychiatric News.

"We also don't know from these data who are the physicians prescribing these drugs," she said.

"Our concern is that these drugs are really not well studied in children, particularly for their effects over the long term."

Psychiatrist Ranga Krishnan, M.B., a co-author on the study, agreed. "We really don't know what these drugs do to physical and mental development over the long term," he said.

He said the study was prompted in part by a local, anecdotal impression that antipsychotic drug use was increasing in the pediatric population.

"Our own assessment internally was showing that use of these drugs was increasing," Krishnan said. "Especially in the emergency room, we saw a lot of kids coming in who were on these drugs. The question was whether this was a local or a national phenomenon."

He added that he believes that use of atypical antipsychotics may have actually increased since the study period. Because of controversy surrounding potential suicide risk associated with SSRIs in children, he said, some physicians may be switching to the atypical antipsychotics.

Like Curtis, he believes that in many cases these drugs are likely being prescribed by nonpsychiatrists. "If you asked most psychiatrists, I think they would be surprised by the findings," he said.

An abstract of "Prevalence of Atypical Antipsychotic Drug Use Among Commercially Insured Youths in the United States" is posted online at .

Arch Pediatr Adolesc Med 2005 159 362

Public release date: 19-May-2005

Contact: John Easton
John.Easton@uchospitals.edu, 773-702-6241
University of Chicago Medical Center

As morphine turns 200, drug that blocks its side effects reveals new secrets

On May 21, 2005, the world of medicine will celebrate the 200th anniversary of the crystallization of morphine in Einbeck, Germany. Since 1805, morphine and its derivatives have become the most widely used treatment for severe pain. Now more than 230 tons of morphine is used each year for medical purposes including pain relief for patients with chronic pain or advanced medical illness and post-operative analgesia.

Although many new pain relievers have been synthesized since the crystallization of morphine from opium almost 200 years ago, "morphine remains the standard against which all new medications for postoperative pain relief are compared," notes Jonathan Moss, M.D., Ph.D., professor of anesthesia and critical care at the University of Chicago.

Despite 200 years of increasingly frequent use however, even the medical uses of morphine still present problems, such as severe nausea, itching, and constipation.

Moss has been invited to speak at the Einbeck morphine-commemorative conference in May on the relationship between morphine and a drug known as methylnaltrexone -- a peripheral opiate antagonist developed at the University of Chicago -- which can prevent many of these troubling side effects.

Moss's lecture, "Morphine's secrets revealed," will focus on how methylnaltrexone enables scientists to distinguish between the central analgesic effects of morphine and its peripheral side effects.

Discovery of morphine

Morphine was discovered by Freidrich Wilhelm Adam Serturner (1783-1841), an obscure, uneducated, 21-year-old pharmacist's assistant with little equipment but loads of curiosity.

Serturner wondered about the medicinal properties of opium, which was widely used by 18th-century physicians. In a series of experiments, performed in his spare time and published in 1806, he managed to isolate an organic alkaloid compound from the resinous gum secreted by Papaver somniferum -- the opium poppy.

Serturner found that opium with the alkaloid removed had no effect on animals, but the alkaloid itself had ten times the power of processed opium. He named that substance morphine, after Morpheus, the Greek god of dreams, for its tendency to cause sleep. He spent several years experimenting with morphine, often on himself, learning its therapeutic effects as well as its considerable dangers. Although his work was initially ignored, he recognized its significance. "I flatter myself," he wrote in 1816, that "my observations have explained to a considerable extent the constitution of opium, and that I have enriched chemistry with a new acid (meconic) and with a new alkaline base (morphium), a remarkable substance."

As he predicted, chemists and physicians soon grew interested in his discoveries. Serturner's crystallization of morphine was the first isolation of a natural plant alkaloid. It sparked the study of alkaloid chemistry and hastened the emergence of the modern pharmaceutical industry.

Other researchers soon began to isolate similar alkaloids from organic substances, such as strychnine in 1817, caffeine in 1820 and nicotine in 1828. In 1831, Serturner won a lucrative prize for the discovery.

In 1818, French physician Francois Magendie published a paper that described how morphine brought pain relief and much-needed sleep to an ailing young girl. This stimulated widespread medical interest. By the mid-1820s morphine was widely available in Western Europe in standardized doses from several sources, including the Darmstadt chemical company started by Heinrich Emanuel Merck.

By the 1850s the first reliable syringes were developed and injected morphine became a standard method of reducing pain during and after surgery. Since then, various delivery systems for morphine have been developed, including epidural injection and pumps that allow patient-controlled analgesia.

Although morphine was originally touted as a cure for many maladies, even for opium addiction, by the 1870s physicians had become increasingly aware of its own addictive properties. Ironically, C.R. Alder Wright, a chemist at a London hospital who was searching for a non-addictive alternative to morphine, came up with a more potent narcotic, diacetylmorphine, in 1874.

Heinrich Dreser, a chemist at Bayer Laboratories developed and tested Wright's new semi-synthetic drug on animals, humans, and most notably himself. Finding that it was a powerful painkiller and appeared effective for a variety of respiratory ailments, Bayer began producing and marketing this drug as an analgesic and a "sedative for coughs" in 1898. Because of its "heroic" ability to relieve pain, they called it heroin.

The medical profession initially welcomed the new drug but soon recognized it's addictive potential. In 1913, Bayer halted production, edited the drug out of their official company history and focused instead on marketing their second blockbuster drug, aspirin.

Discovery of Methylnaltrexone

Yearly, more than 500,000 patients with advanced cancer depend on powerful opioid-based pain relievers such as morphine, or its derivatives OxyContin or Percocet, for pain relief. One side effect of all narcotic pain relievers is severe constipation, which can be so distressing that many patients discontinue their pain medication.

To solve this problem, the late Leon Goldberg, a University of Chicago pharmacologist, developed methylnaltrexone (MNTX). In order to help a friend with morphine-induced constipation, Goldberg modified naltrexone, an established drug that blocks the effects of morphine, so that it could no longer cross the protective barrier that surrounds the brain. Consequently, it did not interfere with morphine's effect on pain, which is centered in the brain, but it did block morphine's effects on gut motility, which are mediated by receptors in the gastrointestinal tract.

Goldberg's university colleagues continued to develop the compound, testing it in animals and performing the initial human safety trials and clinical studies in volunteers and patients.

The University of Chicago licensed the MNTX technology to UR Labs, Inc. and in 2001, Progenics Pharmaceuticals of Tarrytown, NY, sub-licensed the worldwide exclusive rights to develop MNTX from UR Labs. One phase 3 trial of MNTX for treatment of opioid-induced constipation in patients with advanced medical illness has been completed and results from a second trial were reported May 17 at the American Society of Clinical Oncology annual meeting. Progenix has a target date of New Drug Application submission in late 2005.

Meanwhile, Moss and his University colleagues have identified multiple uses of MNTX, beyond the original discovery by Goldberg. Some of these additional uses of MNTX include treatment of post-operative bowel dysfunction (a serious impairment of the gastrointestinal tract following surgery), opioid-induced itching, urinary retention, and possibly HIV.

Opiates appear to increase the ability of HIV to infect certain immune system cells. In 2003, Moss reported that very small amounts of methylnaltrexone blocked these increases. "If our studies are borne out in future clinical trials, methylnaltrexone may improve the care of patients who take opioids for pain caused by AIDS," he said.

"Two hundred years after Serturner's work, we continue to learn a great deal about morphine," Moss said. "The ability to facilitate pain relief while minimizing side effects is both conceptually important and very relevant to patient care."

Believe it or not - penises are often painted on the sides of houses in Bhutan. It recalls one of the tales of Lama Drukpa Kunley, a somewhat unusual figure in Bhutanese Buddhism, who is sometimes known as the Divine Madman.

On one occasion, the Divine Madman was presented with a blessing thread to hang around his neck. However, instead he wrapped the thread around his penis, saying that he hoped it would give him more luck with the ladies!