Vagus Nerve Stimulation Effective in Resistant Depression

Fran Lowry

May 16, 2013

Vagus nerve stimulation (VNS) appears to be effective for treatment-resistant depression and may induce changes in brain metabolism weeks or even months before patients begin to feel better, new imaging research suggests.

"These neuroimaging findings suggest that antidepressant response to VNS has very large and profound effects early on in the cortex of the brain, altering the metabolic activity in cortical regions, in individuals with treatment-resistant depression," lead author Charles R. Conway, MD, of the Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News.

"The regions affected are regions known to be associated with depression, the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior insular cortex.

"These changes in metabolic activity occur prior to any noticeable clinical effects or improvements. The patient does not appear to be getting less depressed, which suggests that the early part of VNS, the first 1 to 5 months, may actually be bringing about changes, or setting the stage, for later clinical effects which will follow 6 months or more," said Dr. Conway

He added that at 12 months, he and his team of investigators also were seeing increases in regional metabolic activity in brainstem regions associated with depression, most especially a region of the brain associated with dopaminergic brain function, the ventral tegmental area.

The study is published online ahead of print in Brain Stimulation.

Profound and Sustained Improvement

Dr. Conway and his team have implanted VNS devices in some 70 treatment-resistant depression patients.

"Although not everyone responds to VNS, we have seen numerous patients experience very profound and sustained improvements in treatment-resistant depression, and many have been doing well for years," he said.

Dr. Charles Conway

"Many of these patients have gone from being essentially incapacitated by depression to fully functional again."

The researchers hypothesized that any treatment that brings about such a profound improvement must have observable brain changes associated with it, and this prompted their neuroimaging study.

In the current study, Dr. Conway and his group followed 13 patients with treatment-resistant depression whose symptoms had not improved despite many months of treatment with as many as 5 different antidepressant medications.

Most of the patients had been depressed for at least 2 years, but some patients had been clinically depressed for more than 20 years.

All patients underwent surgery to have the VNS device inserted. The left vagus nerve runs down the side of the body from the brainstem to the abdomen; once activated, the VNS device delivers a 30-second electronic stimulus to the vagus nerve every 5 minutes.

To establish the nature of the treatment's effects on brain activity, the investigators performed positron emission tomography (PET) brain imaging prior to the initiation of stimulation, and again 3 and 12 months after stimulation had begun.

They then compared these brain scans with each other at different time points.

"We used a form of PET which uses radioactively labeled glucose, fluorodeoxyglucose, or FDG," Dr. Conway explained. "The brain is constantly taking up glucose from the blood stream. If there is a regional decrease in metabolism, typically associated with decreased regional brain activity, this can be detected using FDG-PET, because you see less FDG uptake in a given region."

FDA Approved, But Not Widely Available

Eventually, 9 of the 13 patients experienced improvement in depression with the VNS treatment. However, in most cases, it took several months for improvement to occur.

Among those who responded, the FDG-PET scans showed significant changes in brain metabolism following 3 months of stimulation, and this occurred several months before any improvements in their symptoms of depression were noted.

"We saw very large changes in brain metabolism occurring far in advance of any improvement in mood. It's almost as if there's an adaptive process that occurs. First the brain begins to function differently. Then the patient's mood begins to improve," Dr. Conway said.

Although this study is preliminary and a larger version of this study should be done, these findings suggest that antidepressant responders to VNS undergo changes in brain activity associated with regional metabolic activity changes in regions associated with depression, Dr. Conway said.

"The data also suggest that the eventual VNS-responding state involves activation of brainstem regions associated with dopamine activity," he said.

Despite being FDA-approved for treatment-resistant depression, VNS is not easily available for the general public because insurance carriers will not reimburse for the treatment, Dr. Conway said.

"We believe that this study, like many other recent studies as well as our extensive clinical experience, support our clinical observations that this treatment is effective. Also, this population of treatment-resistant depression patients has very few viable successful treatments, and we believe VNS is both effective and has sustained benefit in a significant subset of patients with TRD, and it should be available to those who need it."

Need for Replication

Commenting on the study for Medscape Medical News, William Bunney, MD, Distinguished Professor and Della Martin Chair of Psychiatry, University of California, Irvine, said that the high response rate in this patient population is "therapeutically interesting and may be due in part to the selection criteria used in this research."

Dr. William Bunney

Dr. Bunney added that the observation that the patients did not relapse during a 12-month period "has important treatment implications in a disorder characterized by recurrent depressive episodes. Although this is a somewhat invasive therapy, it may be justified by the high success rate, particularly if it is replicated in other studies using similar research designs."

Dr. Conway reports financial relationships with Cyberonics, Merck, and Bristol-Myers Squibb. Dr. Bunney reports that he is a member of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by Pritzker Neuropsychiatric Disorders Research Fund LLC. The study was supported by funding from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Alliance for Research in Schizophrenia and Affective Disorders, and the Sidney R. Baer Jr Foundation. Cyberonics (Houston, Texas) donated 3 cost-free devices to participants in this trial.

Brain Stimul. Published online ahead of print February 15, 2013. Abstract


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