January 2007 | Back to Table of Contents

Pulse

Depression-Busting Devices

Magnetic and electronic stimulators may help patients who have failed other treatments for depression.

When Shirlene Sampson, M.D., talks about transcranial magnetic stimulation (TMS) and its potential for helping people who have failed or cannot tolerate conventional treatments for depression, her passion becomes obvious.

“Depression is an extraordinarily painful illness when it is in its most severe form,” she says, adding that about 4 million people in the United States have what’s called refractory or treatment-resistant depression. “People lose their ability to cope and function. They lose their lives. And the patients, families, and treaters get hopeless. They run out of things to do.”

Sampson, a psychiatrist, has been studying TMS as a possible treatment for refractory depression since the late 1990s, when, as a fellow in neuropsychiatry at Harvard University, she worked alongside one of the pioneers in the field. In 1999, she came to Mayo Clinic to set up a TMS lab, which has been involved in a 23-center double-blind, placebo-controlled clinical trial of TMS for treating depression in 301 patients.

The results of the trial, which are being reviewed by the Food and Drug Administration (FDA), show promise for the use of TMS in treating depression. According to findings presented at the American Psychiatric Association meeting in Toronto last May by Neuronetics Inc., the manufacturer of the TMS therapy system, the patients who received TMS therapy in the placebo-controlled trial showed twice the rate of response and remission as those who did not. Of the 85 patients who went on to participate in an open-label study of TMS, 45 percent showed improvement of their symptoms, and 31 percent saw complete remission.

Studies comparing the results of TMS with those of electroconvulsive therapy (ECT), which has been the standard for treating patients with medication-resistant depression, show similar success rates. But Sampson notes limitations in those studies. Unlike ECT, however, TMS doesn’t require the patient to be sedated, nor does it have side effects such as memory loss or confusion. (Fewer than 8 percent of the patients who took part in the TMS study left because they couldn’t tolerate the treatments.)

The most significant advantage of TMS over other technologies that are being tested for treating depression is that it’s not invasive. A magnetic coil is placed over the patient’s skull and delivers brief magnetic field pulses to the cerebral cortex.

Sampson explains that most of the TMS studies have involved applying high-frequency stimulation (5 Hz to 20 Hz) to the dorsal lateral prefrontal cortex. Others have applied very low-frequency stimulation (1 Hz) to the right side of the brain.

“Depression is a very heterogeneous illness,” she says of the possible reasons why different frequencies delivered to different parts of the brain seem to be effective. “You can have someone who is anxious and agitated or who is sleeping all the time and eating everything in sight. People present with different types of disturbances in their brain, yet we call it depression.”

The FDA is expected to decide whether to approve TMS for treatment of refractory depression later this year.

Vagus Nerve Stimulation
One device that does have FDA approval for use in treating medication-resistant depression is Cyberonics Inc.’s vagus nerve stimulator (VNS).

The stimulator is made up of a half dollar–sized battery-operated pulse generator that is surgically implanted under the patient’s skin on the left side of the chest, just below the clavicle. The generator is connected to a bipolar lead that is surgically attached to the vagus nerve in the neck. The pulse generator delivers a small electrical current to the nerve for about 30 seconds every five minutes. As the device stimulates the vagus nerve, the nerve then stimulates the parts of the brain that are responsible for mood.

In a 12-center study of VNS for treatment-resistant depression, investigators found that on 12-month follow up, 30 percent of the 205 patients who received the device plus an antidepressant saw a 50 percent reduction in symptoms compared with 13 percent of a control group of 124 patients who received medications only. In addition, 17 percent of the patients who received VNS therapy achieved remission, compared with 7 percent of those who received medication only. The results were the same after 24 months, and the most common side effect patients complained of was vocal hoarseness.

Despite the fact that the study wasn’t double-blinded or placebo-controlled, the FDA approved the use of the device for treating refractory depression in 2005.

“The rate of remission and response with VNS really could not be described as great,” says Dean Knudson, M.D., a psychiatrist at Abbott Northwestern Hospital in Minneapolis. “But when you compare it with what we could have done previously, it’s a big difference.”

Knudson has referred two patients for implantation of a vagus nerve stimulator in the past year, both of whom had tried and failed electroconvulsive therapy. One of those patients has responded “robustly,” Knudson says; the other has not.

Deep-Brain Stimulation
Another medical device maker, Fridley-based Medtronic, is banking on deep-brain stimulation (DBS) as a possible treatment for refractory depression.

Deep-brain stimulation uses a surgically implantable pacemaker-like device with leads connected to two electrodes that are inserted in the subgenual cingulate region of the brain—the area that modulates negative mood and sadness and has been observed to be metabolically overactive in patients with refractory depression. And like a cardiac pacemaker, the pulse generator regularly delivers a steady stream of electrical impulses. (Researchers are still determining the optimal voltage, pulse width, and frequency.)

Difficult Depression When traditional treatments don’t work. Approximately 4 million people in the United States—20 percent of those with depression—suffer from the treatment-resistant variety. “Most of these patients have failed three or four anti-depressive medications,” says Dean Knudson, M.D., a psychiatrist who works with inpatients at Abbott Northwestern Hospital in Minneapolis. He says some patients don’t respond to medications; others cannot tolerate the side effects of the medications or electroconvulsive therapy (ECT), the standard treatment for those with refractory depression, which is known to cause memory loss and confusion. According to a 2002 study by researchers at the Cambridge, Massachusetts–based MEDSTAT Group, people with treatment-resistant depression often end up hospitalized, and the annual cost of their care runs approximately $40,000. “This is a dangerous condition,” says Knudson, who sees a number of patients with treatment-resistant depression in his practice. “If you have this illness, there is between a 10 and 20 percent chance that you will go on to kill yourself to escape it.”—K.K.

“The foundation of deep-brain stimulation goes back to earlier neurosurgical history where surgeons used to make lesions at different places in the brain for treating movement disorders,” says Paul Stypulkowski, Ph.D., senior director of emerging therapies research for Medtronic’s neurological division.

After stimulating targets in the brain that were previously lesioned for treatment of movement disorders such as Parkinson’s disease, essential tremor, and dystonia and seeing success, researchers decided to try stimulating areas of the brain to treat psychiatric disorders. One of those is the internal capsule, a dense bundle of nerve fibers that carries information between the cortical regions and the thalamus, the brain’s central relay station.

In the late 1990s, researchers tested the device on patients with obsessive-compulsive disorder (OCD). Not only did the patients’ OCD improve, but also those who had co-morbid depression saw significant improvements in their mood.

A handful of centers in the United States and Europe have since begun investigating the use of DBS for patients with treatment-resistant depression. So far, one small trial led by Emory University’s Helen Mayberg, M.D., involved delivering chronic deep-brain stimulation to the brain’s subgenual cingulate region. Results, which were published in Neuron in 2005, showed marked remission in four of six patients.

“Those were very encouraging results,” says Stypulkowski. He says Medtronic is working with the FDA to design a multicenter trial of DBS for treatment-resistant depression that is on track to begin later this year.

Which Patient, Which Treatment?
Exactly who might be the best candidates for each of these emerging therapies remains to be seen. Stypulkowski says that until large-scale, randomized controlled trials of TMS and DBS are complete, investigators won’t know the benefits of each, how the results of these therapies compare with those of ECT, and, in the case of DBS, whether the benefits are worth the risk associated with having electrodes implanted in the brain.

Sampson believes TMS may become the first option for patients who have failed psychotherapy and medications because it is noninvasive and is tolerated better than ECT.

In addition to giving hope to patients who previously had very little, Sampson says studying these therapies is also helping investigators gain insights into what causes depression. “Depression was seen as a deficiency of serotonin, dopamine, and noradrenaline,” she says. “Now we have functional MRIs, which can look at the brain more directly and help us understand which parts are not working right when folks are depressed and then reimage them when they’re better to see how the brain has changed. By doing that, we can start to get at the very diverse structures of the brain that are involved in depression.”—Kim Kiser