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.