Finding effective therapeutic options for patients with difficult-to-treat,
or treatment-resistant, depression remains a significant challenge. yet
encouraging progress with two nonpharmacologic treatment options—vagus
nerve stimulation (vNS) and transcranial magnetic stimulation (TMS)—may
soon offer more choices of safe and effective treatments that represent
substantial improvements over traditional electroconvulsive therapy and/or
A series of presentations during APA's 2006 annual meeting in May gave
attendees a firsthand look at new data from company-sponsored research on the
efficacy and safety of vNS in patients with treatment-resistant depression who
have failed at least four adequate trials of antidepressant therapy, as well
as company-sponsored clinical trials data submitted to the FDA in support of
the efficacy and safety of TMS.
Indeed, both Cyberonics Inc., which markets the vNS system, and Neuronetics
Inc., which hopes to win FDA approval to market the TMS system, were highly
visible at the annual meeting. Both companies had representative clinicians
and researchers working with each system at the meeting and presented new data
on short-term as well as longer-term efficacy of each of the"
therapeutic neuromodulation" techniques, along with safety data,
during new research poster presentations, symposia, and workshops.
According to Cyberonics, the company has trained more than 5,000
psychiatrists in the use of the vNS system, and more than 10,000 patients have
been identified as potentially appropriate candidates for vNS therapy. About
180 different payers have approved coverage of vNS therapy, on a case-by-case
basis, for about 1,100 patients. The company also estimates that about 4,700
patients have been denied coverage for vNS therapy since its July 2005
FDA approval of vNS therapy quickly became controversial when the director
of the FDA's Center for Devices and Radiological Health overruled subordinates
and approved the vNS system for use. FDA reviewers had recommended that the
system not be approved, while the FDA advisory board voted narrowly to
recommend approval. In the end, vNS was approved "for the adjunctive
long-term treatment of chronic or recurrent depression" in adult
patients who "have not had an adequate response to four or more adequate
antidepressant treatments" (Psychiatric News, August 19,
The vNS system requires the surgical implantation of a pacemaker-like nerve
stimulator under the skin in the abdomen or shoulder and the"
tunneling" of stimulation wires into the neck, where they are
wrapped around the vagus nerve. When turned on, the computer-driven stimulator
delivers periodic electrical stimuli of a predetermined intensity to the vagus
Results from several analyses were released during the annual meeting,
including an analysis of suicidality and worsening depression during two years
of vNS therapy as an adjunct to pharmacotherapy. That analysis, by William
Burke, M.D., a professor and vice chair of psychiatry at the University of
Nebraska Medical Center, followed 235 patients over 24 months. In the overall
group 205 received vNS therapy, while 30 patients received "treatment as
Researchers compared data on suicides, attempted suicides, suicidal
ideation, and hospitalizations due to worsening depression comparatively in
the two groups. Suicidality (a composite of all three suicide measures) and
hospitalizations for worsening depression declined over the 24-month study in
those on vNS therapy. In comparison, those receiving treatment as usual saw
slight increases in the tracked outcomes or no change over time.
The two-year study was one of several indicating that the therapeutic
effects of vNS occur over time. A second analysis presented data from a pilot
study in which positron emission tomography (PET) images were obtained three
months after implantation of the vNS system, then again at six, 12, and 24
months after initiation of vNS therapy. Eight patients stayed in the small
study through their six-month scans, six patients completed the 12-month scan,
and four patients completed all scans, including the 24-month scan.
Charles Conway, M.D., an assistant professor of psychiatry at St. Louis
University School of Medicine, who led the imaging study, said that the images
revealed that it takes between three and 12 months before vNS appears to
change brain activity. These changes "roughly parallel" the
significantly delayed improvements that study psychiatrists observed in the
patients' mood, Conway noted in a press release.
The study also showed, however, that "about 70 percent of patients
who get better from vNS at one year stay better at two years," Conway
added. "That is unheard of in a depressed population this severe and
suggests that the brain changes induced by this treatment appear to be
Cyberonics also announced at the annual meeting that it is initiating a
study to evaluate long-term clinical and economic outcomes for patients with
treatment-resistant depression who receive vNS therapy. The study will include
a comprehensive review and analysis of existing data on clinical and economic
outcomes associated with the use of vNS compared with the outcomes of
treatment as usual without vNS therapy.
A second initiative is Cyberonics' launch of a patient registry of
treatment-resistant patients who receive vNS therapy. The registry, which will
be administered by Martin keller, M.D., a professor and chair of psychiatry at
Brown University, currently involves 22 medical centers across the country and
may involve up to 100 centers that will enroll 2,000 patients in the registry.
The longitudinal, prospective, observational registry will track clinical
course and outcomes for patients with vNS and without.
Neuronetics Inc. released results of the first multicenter, controlled
clinical trial of its transcranial magnetic stimulation (TMS) therapy at a
symposium at APA's annual meeting. In contrast to the invasive nature of vNS
(which requires surgical implantation), TMS is noninvasive (Psychiatric
News, July 1, 2005).
During a TMS therapy session, a patient sits in a chair similar to those
found in dental offices with the TMS machine directed at the patient's skull
over the left prefrontal cortex. The device looks similar to a dental X-ray
machine. The TMS apparatus uses a strong, highly focused magnetic
field—much like MRI technology—to create a focal electrical
current in the brain tissue. The therapy does not require anesthesia or
sedation, so patients can drive themselves home immediately following their
The "NeuroStar TMS therapy system" is currently under review by
the FDA, with an approval anticipated by Neuronetics sometime around early
2007, said Mark Demitrack, M.D., a vice president and chief medical officer at
The company's pivotal trials of TMS therapy involved 301 patients with
depression who were unresponsive to at least one previous adequate
antidepressant therapy at 23 clinical research institutions in the United
States, Canada, and Australia. Previously, TMS had been studied (for about a
decade) in small, single-site studies with small numbers of patients.
Neuronetics completed two studies lasting four to six weeks, the first an
acute efficacy and safety trial including a double-blind "sham
TMS" control. In sham TMS, internal modifications were made to shield
the TMS system magnet so that therapy with random patients would outwardly
appear to progress normally but no magnetic stimulation could reach their
brains. The system modifications were made by persons not involved in the
clinical aspects of the trial. Neither the patients nor the clinicians knew
whether specific patients were in the active therapy group or in the
A second four- to six-week study was also conducted with an open-label,
crossover design with the patients who did not respond to the double-blind
sham-controlled trial. Then, all patients who improved (defined as at least a
25 percent decrease from baseline in total score on the Hamilton Depression
Rating Scale-17 Item at study completion) in either of the four- to six-week
trials were entered into a "maintenance of antidepressant effect"
trial lasting six months.
Overall, patients studied were in a recurrent episode of major depressive
disorder and were roughly equal in terms of gender, averaged 48 years of age,
and had a mean duration of their current depressive episode of about 13
months. The average number of verified antidepressant treatment failures per
patient was 1.6 for the current depressive episode. The patients were severely
depressed, with average Montgomery-Asberg Depression Rating Scale scores
around 33 and Hamilton scores around 23.
Patients receiving active TMS improved significantly more than the sham
patients by week 4. Response rates in the active group were generally about
two-fold higher than those with sham-TMS by week 4, and remission rates were
also about two-fold higher in the active group compared with the sham group by
week 6. Reflecting the severity of the patients' illness, placebo response
rates were low, averaging 11 percent at week 4 and 13 percent at week 6.
Importantly, in the six-month extension study, efficacy was well maintained
through the end of the study. TMS, even at high-intensity administration, was
safe with no seizure activity in any patients, no negative auditory or
cognitive effects, and a general absence of typical side effects of
The most frequent treatment-emergent adverse events associated with active
TMS, compared with sham-TMS, were pain at the application site, including
facial discomfort or pain, toothache, skin pain, and muscle twitching.
While the data continue to be very favorable, the clinical urgency to help
patients with treatment-resistant depression remains, Neuronetic's Demitrack
said, especially in light of the recent reports from the National Institute of
Mental Health's STAR*D study of pharmacotherapy of treatment-resistant
Neuronetics' data show a comparable degree of efficacy with STAR*D level 2
data, "albeit with a greater degree of treatment resistance and a much
reduced adverse-event burden," Demitrack told Psychiatric
TMS has broad effects on brain activity, as well as in specific areas of
the brain associated with mood, Demitrack added. Most of the therapeutic
effects of TMS appear to involve dopamine; however, lesser effects have been
noted with serotonin and norepinephrine.
"As such, TMS may have different or added long-term effects,"
Demitrack concluded. "TMS may also have implications for other uses, in
other psychiatric disorders such as schizophrenia, and possibly
obsessive-compulsive disorder, as well as in nonpsychiatric disorders such as
epilepsy, chronic pain, and poststroke rehabilitation." ▪