Aiming to stimulate better outcomes

Behavioral healthcare professionals have been trying to help patients with treatment-resistant depression (TRD) since the dawn of modern psychotherapy. Antidepressant medications and modern electroconvulsive therapy (ECT), in conjunction with psychotherapy, have been used to treat patients with TRD, but many patients remain so severely depressed that they are nonfunctional or barely functional. Yet several new therapies, which involve applying electrical or magnetic stimulation to the brain, are offering providers and patients hope.

Vagus Nerve Stimulation

The furthest along is vagus nerve stimulation (VNS), which the FDA approved in 1997 for the treatment of epileptic seizures and in 2005 for TRD. In VNS, electrical stimulation is carried to the vagus nerve on the left side of the neck by thin, flexible wires connected to a pulse generator (similar to a pacemaker) implanted in the patient's chest (figure 1). The vagus nerve, in turn, delivers electrical pulses to the areas of the brain involved in mood regulation, including those that produce serotonin and norepinephrine.


Figure 1. Image courtesy of Cyberonics, Inc. The device (marketed by Cyberonics, Inc.) costs approximately $15,000, and surgery costs about $10,000 (depending on individual hospital charges). Surgery is largely benign, and side effects from VNS tend to be minor: Some patients develop hoarseness or a tremor in their voice, but patients can manually block stimulation for short periods if required.

Mark Rapaport, MD, a psychiatrist at Los Angeles's Cedars-Sinai Medical Center involved in the VNS for TRD clinical trials, says VNS “is for people who have been robustly treated with face-to-face therapy and pharmacotherapy but still don’t respond. These folks have a greater chance of hurting themselves.”

Yet questions surround the efficacy of VNS for TRD. Opposition to VNS for TRD points to the two major trials of VNS for TRD. The main trial, involving 235 patients, they note, showed no statistically significant difference between those treated with VNS and a control group. In a second study, 30% of 174 VNS recipients showed significant improvement after one year, but the study lacked a control group and patients received other depression treatments in addition to VNS after implantation.1,2

Dr. Rapaport says that a 20 to 30% improvement in symptoms is significant for TRD patients, many of whom are occupationally and socially nonfunctional or barely functional.

“I deal with a fair number of patients who are treatment resistant, and I have a favorable impression of VNS,” says Francisco Moreno, MD, director of the molecular psychiatry laboratory at the University of Arizona's Arizona Health Sciences Center and an associate professor of psychiatry at the university. He also was involved in the multicenter clinical trials for VNS. He adds that with VNS, “It's more like a partial improvement in symptoms, but [patients] and their families will tell you that even mild improvement makes a difference for them. When you’re dealing with chronic depression that's severe and doesn’t respond to other forms of treatment, we gauge outcomes differently. It's extremely rare to get these patients to 100% improvement.”

VNS is “a comparatively effective therapy,” notes Donald Dunner, MD, director of the Center for Anxiety and Depression and a professor of psychiatry and behavioral sciences at the University of Washington, Seattle. VNS doesn’t produce “the 70% response rate that you’d like to see for never-treated depressed patients when you start them on their first treatment, but for this group, it offers them more hope than anything out there.”

The FDA itself has been divided on VNS for TRD. The agency originally rejected Cyberonics’ request for approval, but in July 2005 Daniel G. Schultz, MD, director of the FDA's Center for Devices and Radiological Health, overruled unanimous opposition by 20 of his staff members to approve VNS for TRD, which prompted a Senate investigation.1,2 Dr. Schultz cited the lack of TRD treatments in making his decision, and an FDA advisory panel had recommended approval.

Critics say that public and private payer reimbursement for VNS therapy should be questioned. While Drs. Rapaport, Moreno, and Dunner all say they believe some degree of discrimination against mental healthcare is at work in the case-by-case review of payment for VNS therapy, skeptics counter that mixed clinical trial results justify such an approach.

For their part, insurers have not been rapidly embracing VNS for TRD. Cyberonics notes that more than 1,100 patients with TRD have been treated with VNS therapy, and more than 186 private payers and Medicare have reimbursed providers for the therapy at least once. Yet the company also confirms that neither Medicare nor any private health insurer has issued a blanket policy approving VNS for TRD, which proponents say smacks of discrimination against treatment for mental illness since VNS is nearly universally approved for epilepsy.

Transcranial Magnetic Stimulation

Two additional brain-stimulation therapies are on the horizon. Further along in development is transcranial magnetic stimulation (TMS), which has gone through initial small-group trials and is set for a major multicenter clinical trial that could lead to FDA approval.

In TMS, a conscious patient is seated in a chair (much like a dentist's chair) and an overhead instrument aims short pulses of magnetic energy into the patient's left prefrontal cortex (figure 2). The energy fires specific groups of neurons aimed at areas of the brain thought to control mood. TMS is noninvasive and should be relatively inexpensive to administer. Based on small-trial experience, most patients probably will receive a series of 18 to 20 half-hour sessions during four to six weeks, which could be administered by a trained nurse or physician assistant under a physician's supervision.

Initial results have been positive, says John O’Reardon, MD, assistant professor of psychiatry at the University of Pennsylvania and director of the Treatment-Resistant Depression Clinic at the Hospital of the University of Pennsylvania, Philadelphia. Dr. O’Reardon, one of the leading psychiatric researchers of TMS, was the principal investigator for a recent multicenter clinical trial for the therapy. Compared with a control group not given TMS, patients treated with TMS at 23 participating centers in the United States, Canada, and Australia did significantly better at weeks 4 and 6, he reports, with treated patients having on average 75% better depression scores than the control group, and twice as many going into remission. Earlier this year, the commercial developer of TMS, Neuronetics, Inc., applied to the FDA to conduct a nationwide clinical trial for the treatment (marketed as NeuroStar).

Figure 2. Image courtesy of Neuronetics, Inc.

“This will be a very attractive treatment for those who don’t want surgery or additional medications or don’t do well with those,” Dr. O’Reardon says. “And this is something patients can do in their doctor's office.” In fact, he predicts that if the FDA approves TMS, many TRD patients first will choose to try TMS before VNS, given the option of not undergoing surgery.

Deep Brain Stimulation

Another treatment being developed for TRD is deep brain stimulation (DBS), which involves the implantation of electrodes into specific parts of the brain. Nickel-sized holes are drilled into a patient's skull to place the electrodes, which are connected by wires to pacemakers implanted in the patient's chest.

DBS originally was explored in patients with obsessive-compulsive disorder, through a partnership between Butler Hospital, Brown University, and the Cleveland Clinic, explains Donald A. Malone, Jr., MD, head of Adult Psychiatric Services at the Cleveland Clinic. Dr. Malone says that not only did OCD symptoms improve, but so did comorbid depression.

The trials with DBS for TRD have been small, involving only nine patients between the institutions in two years. But anecdotal reports have been noteworthy. Take the case of Cindy Warren, as reported by Cleveland's daily newspaper.3 Warren had such severe TRD that she had attempted suicide and was nonfunctional. Warren, one of Dr. Malone's patients, has had a 90% improvement since her DBS treatment began. “She went from 32 on the Hamilton Scale to about 3, which is probably you and me on a good day,” he notes.

Since her surgery, Warren and her husband have gone snorkeling in the Cayman Islands and hiking in Utah. In fact, Dr. Malone says all of his DBS patients have improved.

DBS still has a way to go before FDA approval for TRD. (In 1997, the FDA approved DBS for treatment of tremors related to Parkinson's disease.) Dr. Malone says the next step will be a large, multicenter trial, which could come in the next couple of years. Medtronic, Inc., has announced that it will fund such a study. Thus DBS eventually could become another tool in the TRD armamentarium.

Ultimately, when it comes to any of these TRD treatments, all those interviewed for this article agree that policymakers—and payers—should consider not only the possible quality-of-living benefits, but also their impact on society in terms of economic productivity and healthcare costs. “One of our patients had spent 89 days out of a previous year in the hospital,” Dr. Malone notes. “After DBS, she went to zero days in the hospital this past year…. That translates into a large number of saved healthcare dollars as well, if you can keep people out of the hospital for significant periods.”

Mark Hagland is a freelance writer.

References

1. Boodman SG. Mood machine. Washington Post. March 21, 2006: HE01.
2. Harris G. Device won approval though F.D.A. staff objected. New York Times. February 17, 2006.
3. Treffinger S. Fixing the heart of depression. The Plain Dealer. April 25, 2006:A1,A7.