June 16, 2004 -- An FDA advisory panel has tentatively recommended that the FDA approve an implantable electrical nerve stimulator device to treat severe depression.
But committee's 5-2 vote for FDA approval hinged on several conditions, including restricting the device to patients with severe depression who have not responded to other treatments.
The device has been used since 1997 to treat patients with treatment-resistant epilepsy. Since then, more than 22,000 patients have received the implanted device, called vagus nerve stimulation (VNS), according to the company.
Cyberonics Inc., the device's manufacturer, asked advisors to recommend the FDA's go-ahead for the device in light of studies suggesting that it can help ease depression in some patients who use it for one to two years. Cyberonics is a WebMD sponsor.
VNS consists of a pacemaker-like device the size of a stopwatch that a surgeon implants in a patient's upper chest. Wires attach the device to the vagus nerve, which runs from the neck into the brain. It's thought that the vagus nerve provides electrical impulses to areas of the brain believed to be important in regulating mood. The device is implanted during a surgical procedure; the recipient can usually go home the same day.
Once implanted, the device delivers electrical pulses to the vagus nerve every few seconds, thereby stimulating the brain. The company says it intends the device only for adult patients with severe depression that has not improved after treatment with antidepressant drugs.
Data submitted by Cyberonics showed little improvement in depression symptoms after patients used the device for three months. But company officials point to data showing that 18 of 59 patients showed at least a 50% improvement in depression after one year of use. Twenty-five out of the 59 showed improvements after two years.
Officials argue that the improvements are especially beneficial since many severely depressed patients fail to reliably take medication and often do not show long-term improvements with antidepressant drugs.
"This alone I think is a significant benefit of VNS therapy," says Richard J. Rudolph, MD, Cyberonics' chief medical officer.
Experts say they are encouraged by the data, but not all were convinced that VNS is effective.
"I think there are certainly hints to efficacy. I think it's not been proved," says Kyra J. Becker, MD, a neurologist at the University of Washington School of Medicine in Seattle and chairwoman of the FDA panel.
Some experts also express worry that the company had not done enough to show that VNS was responsible for the improvements in depression symptoms. Many patients in the trial knew that they were receiving VNS stimulation, making them vulnerable to a placebo effect. Patients in the studies were also allowed to take antidepressant drugs and other medications, which could have skewed the results, they say.
Some panelists asked the company to go back and perform a randomized trial of patients with VNS against those receiving a sham surgery in which no stimulation is delivered.
"We can guess all we want, we can speculate. But I don't find this at the acceptable level of a randomized, controlled trial," says Richard P. Malone, MD, a professor of psychiatry and epidemiology at Brigham and Women's Hospital in Boston and a member of the panel.
The committee asked the FDA to require labeling that confines VNS to patients who have gotten no benefit out of at least four existing medical depression treatments. They also want the FDA to require that psychiatrists receive special training before using the device to treat patients.
Safety in Question
Up to two-thirds of patients using VNS for depression or epilepsy experience alterations in their voice because of the electrical pulses to the vagus nerve. Many patients also experience mild side effects including persistent cough. Patients can deactivate the device with a magnet if they become uncomfortable or want to alleviate the voice alterations.
About 1% of patients using the device for epilepsy have to have it removed due to infections, according to the company.
But the experts are more uneasy about suggestions that the implants may carry risks for some patients. Thirty-one patients in one study of 235 subjects had episodes of deepening depression, and many had two or more episodes of worsening depression, according to the company.
Twenty-five patients using VNS also attempted suicide in several company studies. The experts acknowledge that suicide is a common risk in severely depressed patients but say they are still worried about the product's safety.
"There's enough to make us concerned that there might be something to participation in suicide with this device," says Michael J. Schlosser, MD, an FDA medical officer.
Some members of the advisory panel urged the company to perform more randomized studies comparing patients using VNS to those getting traditional antidepressant treatment.
Others cautioned that requiring more studies could deprive very sick patients for whom other treatments do not work.
"I'm concerned about the potential burden to patients who might not be able to receive a viable treatment for this very severe illness," says Fochtmann, a psychiatrist from the State University of New York in Stony Brook.
A. John Rush, MD, a psychiatrist at the University of Texas Southwestern Medical Center in Dallas and a Cyberonics consultant, says approving VNS is appropriate even though the company did not submit a randomized, controlled study as is customary with most FDA approvals.
"If we help one in four or one in five ... that is a home run in a patient population where we just don't see [improvement] in the long run," he says.