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Nondrug Depression Treatments Show Promise for Certain Patients

Advances in existing and novel brain stimulation therapies are aimed at providing significant relief to the 4 million Americans with treatment-resistant depression.

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 polypharmacy.

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 approval.

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, 2005).

Pacemaker-Like Device Used

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 nerve.

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 usual."

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.

Brain Changes After Several Months

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 long-lasting."

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.

TMS Data Look Promising

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 40-minute treatment.

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 Neuronetics.

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 sham-control group.

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 antidepressant medications.

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.

Clinical Urgency Remains

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 depression.

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 News.

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."

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