For almost a decade, patients suffering from some forms of epilepsy have received the benefit of vagus nerve stimulation (VNS) therapy. In July 2005, the Food and Drug Administration approved the use of the device for the most severe cases of treatment-resistant depression.
Dr. Richard L. Rudolph, vice president of clinical and medical affairs and the chief medical officer for Cyberonics, the Houston-based manufacturer of the device, says FDA approval for the treatment of patients with refractory epilepsy came in 1997, and the following year clinical trials for depression were launched.
"The first hint or impetus to pursue that area came from anecdotal reports from patients in the epilepsy clinical trials. They began reporting significant improvements in mood above and beyond what would normally be expected from their improvement in seizures," he says.
Rudolph adds that from there, different lines of reasoning came into play including delving deeper into the knowledge that anticonvulsants are sometimes used to augment or boost antidepressants. The clinical trials that led to United States approval of the device for treatment-resistant depression ran from 1998-2004, with the FDA signing off on the treatment 14 months ago.
An adjunctive therapy, VNS is meant for use in the toughest cases.
"The labeled indication for VNS therapy requires that a patient must have failed four standard therapies that were judged to be adequately delivered in order to be a candidate," Rudolph says of the stringent nationwide standards. He adds that the treatment is meant for those with chronic depression — as defined by two or more years of depression — or for patients with recurrent depression who have had multiple depressive episodes during their lifetime.
While the diagnosis would typically come from a psychiatrist, a surgeon performs the actual implant. The one-to-two-hour procedure performed under general anesthesia requires two incisions.
The first is on the left side of the neck. "That's where the surgeon wraps the end of the leads … or electrodes … around the vagus nerve," explains Rudolph. The second incision, he continues, is in the chest area (more specifically either under the left collarbone or behind the first fold of skin in the armpit) where the pulse generator is placed in a pocket created under the skin.
The surgeon then tunnels back from the neck to the pocket to connect the lead wires to the pulse generator and activate the stimulation therapy. For patients worried about scarring, Rudolph notes that a surgeon skilled in cosmetic technique can take advantage of the natural creases in the neck to hide the incision. The therapy also seems to have minimal side effects and does not cause the sedation, weight gain or impairment in cognitive function that is linked to some medications.
Once activated, he continues, "The generator applies a mild electrical pulse to the left vagus nerve, and that pulse stimulates the left vagus nerve to send signals up to the brain, eventually reaching areas that are responsible for the regulation of mood."
Rudolph adds, "We're essentially using the vagus nerve as a gateway or a path into the brain."
The areas affected include the limbic and cortical circuitry or networks. "Eventually what happens is you can modulate activity in these areas that improve mood," Rudolph notes.
Typically, relief of symptoms is not immediate. Rudolph says the pattern they have observed in studies is that there is a growing amount of response over time up until about a year.
Dr. Charles R. Conway, a practicing psychiatrist and an assistant professor in the department of psychiatry at Saint Louis University School of Medicine, says they have actually seen additional responsiveness even after that point, and notes that it is realistic to expect VNS therapy to take six months or more before seeing results.
He says that at SLU, they often tell patients to give it two years, while varying currents of stimulation are tweaked.
"We don't really know what the optimal treatment parameters are yet," he says, noting that in the clinical trials some patients responded with tiny doses of currents while others received much higher currents to no avail, leading investigators to believe there is some individual variability in optimal dosing.
In clinical trials, about half of the patients had at least a partial response as defined by symptom improvement of 25 percent or more. At the one-year mark, 27 percent of patients in the clinical trial were identified as responders, as defined by 50 percent or more improvement in their symptoms, and one in six of the total population (16 percent) were remitters with few or no symptoms of depression.
Conway, who was principal investigator at SLU, notes that these results compare to only 13 percent response and 7 percent remission rates for the patients who continued "treatment as usual" without VNS therapy. He adds that the VNS therapy results are more impressive when taking into account that the target audience has been predefined as treatment-resistant.
"These are the sickest of the sick. These are people who have failed on numerous drugs, and many had run the gamut of options," Conway says.
Another plus of the therapy is the long-term positive outcome for those who respond. Conway says that within this difficult-to-treat subset of depression, even when another therapy seems to initially work, it tends to lose effectiveness over time. Rudolph concurs that the "missing element" for this population has been finding a therapy that demonstrates a durable benefit.
"We have people at our site who have been depression-free for four years, which is a big deal," Conway notes of his clinical experience with VNS therapy.
While both Rudolph and Conway underscore the therapy doesn't work for everyone … it can be life changing for those who do respond.
"If you're fortunate enough to be one of the people who get better, there's a very good chance you'll stay well, and you can't really say that about any other treatment for this severe version of depression," Conway concludes.
