Study Expands on Vagus Nerve Stimulation for Depression

Study Expands on Vagus Nerve Stimulation for Depression

In response to encouraging results from a small pilot study of vagus nerve stimulation (VNS) for treatment-resistant depression, researchers are now expanding the study to approximately 200 patients in 20 sites across the United States.

In a statement to the press from Stanford University, one of the research sites added to the initial four, John Barry, M.D., emphasized that the patients being recruited are those with depression that has been refractory to previous treatment strategies. "This population often is given ECT [electroconvulsive therapy], which has a high relapse rate," Barry said. "We hope with this [VNS] device that the efficacy can be maintained over time."

The University of Pittsburgh, another newly added study site, released a statement to the press in which Robert Howland, M.D., commented, "Outside of electroconvulsive therapy, there is almost nothing a doctor can do for someone with TRD [treatment-resistant depression]. This [VNS appliance] is a simple device that, if effective, will dramatically improve the quality of life for people with TRD."

The VNS will be accomplished with an implanted multiprogrammable pulse generator, the Neurocybernetic Prosthesis System (NCP) manufactured by Cyberonics, that is currently approved for use in the treatment of epilepsy. Its possible application for depression was initially suggested after mood improvement was observed in patients receiving VNS for management of medically refractory partial-onset seizures. In addition, the success of applying anticonvulsant medications to stabilize mood suggests that an antiepileptic device may also affect mood.

Interestingly, the use of ECT for depression was originally considered after observing mood improvement that followed seizure episodes in patients with epilepsy, according to a commentary on VNS by Jerrold Rosenbaum, M.D., from Massachusetts General Hospital, and George Heninger, M.D., from Yale University School of Medicine. Rosenbaum and Heninger (2000) explained that there is now a growing body of circumstantial evidence on the efficacy of VNS for depression, including positron emission tomography (PET) indication of limbic activation and determination of alterations in several neurotransmitter systems involved in mood regulation.

They cautioned, however, that some other innovative and promising treatments for depression have ultimately been proven noneffective in large, well-controlled trials, and they welcomed the prospect of such an expanded study of VNS. "The potency of a placebo that combines novelty, surgery, and electrical stimulation is likely to be quite high," they observed, "but no doubt mitigated to some extent by a chronic and refractory condition."

Neuropsychiatric effects of VNS are likely to occur through the afferent sensory connections of the vagus, a mixed afferent sensory and efferent motor nerve, to regions of the brain implicated in neuropsychiatric disorders, according to Mark George, M.D., from Medical University of South Carolina, and colleagues (2000). "These connections reveal how vagus nerve stimulation might be a portal to the brainstem and connected regions," they indicated. "These circuits likely account for the neuropsychiatric effects of VNS, and they invite additional theoretical considerations for potential research and clinical applications."

George et al. cited evidence that VNS prompts changes in norepinephrine and serotonin, the neurotransmitters most closely associated with mood regulation, as well as GABA and glutamate. They noted that VNS can activate the locus ceruleus, the main source of central nervous system norepinephrine-containing neuronal cell bodies, and is associated with increased cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a serotonin metabolite.

The researchers also observed that there has been a historical association of autonomic nervous system dysfunction mediated by the vagus, including heart rate variability, in patients with depression. They speculated, "If depressed patients have abnormalities in brain regions that control the vagus nerve (top-down regulation), then stimulating the vagus nerve might theoretically engage this dysfunctional circuit (a bottom-up approach)."

John Rush, M.D., from University of Texas Southwestern Medical Center, Dallas, and colleagues in the VNS Study Group (2000) identified 30 outpatients with non-psychotic, treatment-resistant major depression or bipolar depression to receive the NCP system. Patients in this open-label, non-randomized pilot study conducted at four sites previously failed to respond to at least two trials of antidepressants of different classes and had no substantial improvement after at least six weeks of psychotherapy. Patients included in the study exhibited baseline scores on the 28-item Hamilton Depression Rating Scale (HAM-D-28) of 20 or more. The patients with bipolar depression (four=bipolar I, five=bipolar II) were either resistant, intolerant or had a medical contraindication to lithium.

Antidepressant medications taken before the study were continued throughout the study period. The NCP was not activated for two weeks after implantation, although patients were told that it might be. After the initial two weeks, the output of the NCP was progressively increased to a maximum level that was comfortably tolerated and within the range used in epilepsy and maintained for an additional eight weeks, with reduction in output if necessitated by side effects. Over the course of the study the pulse parameters were an output current of 0.25 mA to 3.0 mA, 20 Hz to 30 Hz frequency and 250msec to 500 msec pulse width, with 30-second stimulation intervals every three to five minutes.

The NCP appliance is connected and delivers electrical signals to the left vagus nerve, rather than the right which is associated with cardiac ventricular function. In clinical trials of the NCP for epilepsy, Holter monitoring indicated no significant changes in cardiac functioning in more than 250 patients. In this trial, no patients discontinued the study due to adverse events, and the events occurring from implantation and stimulation were generally those expected from previous epilepsy trials.

Rush et al. reported that 40% of these patients, who were previously unresponsive to antidepressant treatment, achieved at least a 50% reduction in HAM-D-28 score from baseline in the acute study period. Six of the 12 patients so responding had done so by week 5 following implantation, after only three weeks of active VNS. No patients improved during the initial two weeks after implantation when there was no active VNS. Seventeen percent of patients were deemed to have completely responded, with an HAM-D-28 score below 10.

At the American Psychiatric Association Meeting in May 2000, the researchers reported on nine months of follow-up, with 11 of the 12 acute phase responders and 16 of the 18 acute-phase non-responders (Marangell et al., 2000). The antidepressant response was maintained in nine of the 11 (91%) patients who initially responded to VNS. Six of the 16 (38%) patients who initially had not responded subsequently improved sufficiently to meet response criteria during the nine months of follow-up.

In their review of VNS, George et al. (2000) noted that the cost of the NCP system is approximately $9,200 for the generator and electrode. Surgical and hospital costs for implantation may vary from $12,000 to $25,000, depending on whether accomplished by inpatient or outpatient surgery. After implantation, the costs incurred are those for office visits for adjustment of VNS settings by personal computer and attached programming wand.

The costs of the VNS procedure for treatment-refractory epilepsy have been covered by insurance programs, and George and colleagues anticipate that the procedure could be similarly supported for treatment-resistant depression. They point out that the cost of VNS compares favorably to the $10,000 to $30,000 for an acute and maintenance course of ECT.

With these encouraging results, the expanded study of VNS for treatment-resistant depression began enrolling additional study patients at the original pilot sites in July of last year, and 16 other sites were enrolling by December to constitute a study population of 200 patients. Physicians wanting to refer patients for possible inclusion may obtain the name of the nearest study physician from Cyberonics. 4/01


1.George MS, Sackeim HA, Rush AJ et al. (2000), Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry 47(4):287-295 [see comment].
2. Marangell LB, Rush AJ, George MS, Sackeim HA (2000), Vagal nerve stimulation in depression. Poster presented at the 153rd annual meeting of the American Psychiatric Association. Chicago, May 17.
3. Rosenbaum JF, Heninger G (2000), Vagus nerve stimulation for treatment-resistant depression. Biol Psychiatry 47(4):273-275.
4. Rush AJ, George MS, Sackeim HA et al.(2000), Vagus nerve stimulation (VNS) for treatment-resistant depression: a multicenter study. Biol Psychiatry 2000 47(4):276-286 [see comments].
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