How VNS brings about an antidepressant effect in TRMD is not known; however, brain imaging studies demonstrate that changes occur with sustained VNS. Nahas and colleagues16 had previously shown changes in functional MRI scans that occurred over many months of stimulation—at approximately 7 months of stimulation. More recently, PET was used to study the changes in regional metabolic activity in the brains of 14 patients with TRMD who had a VNS implant.17 Response to VNS was seen at 12 months.
Brain PET scans were obtained at baseline and at 3 and 12 months of stimulation. Interestingly, subacute (3 months) stimulation was associated with very profound decreases in right-sided regional cerebral metabolic activity in the dorsolateral prefrontal cortex and medial prefrontal cortex, regions known to be associated with depression. In contrast, 12-month regional metabolic activity in these regions did not differ from baseline. There was a large increase in brainstem (midbrain region, localized to the ventral tegmental area) regional cerebral metabolic activity at 12 months in responders, but not in nonresponders. Although these findings are preliminary, they suggest that brainstem regions associated with response in VNS may be activating dopaminergic brainstem regions, because the ventral tegmental area is a primary region of dopaminergic cell bodies.
The future. Despite multiple clinical trials that have shown the antidepressant efficacy of VNS in TRMD, and FDA approval for this indication, the Centers for Medicare and Medicaid Services (CMS) will not reconsider their noncoverage of TRMD, which has been in effect since 2007. This will continue to limit patients’ access to this treatment, because many private insurance companies fall in step with CMS decisions regarding coverage. Under Medicare, some TRMD patients who have had sustained response to VNS will not be eligible to have their devices replaced when the battery runs out. Without insurance coverage, they will not be able to afford a new device.
Given the poor prognosis of TRMD (11.6% response to treatment as usual at 1 year) along with new and compelling evidence regarding VNS efficacy in TRMD, we believe that VNS should be covered by Medicare and private insurance.18 We have experienced considerably higher success rates with VNS in carefully selected TRMD patients (screening out for personality disorders and concomitant substance abuse or dependence). Additional studies are needed to ascertain the mechanism of VNS in TRMD and which patients are most likely to respond to this novel treatment.
Deep brain stimulation
Treatment overview. DBS is being evaluated as an option for TRMD.19 DBS uses stereotactically implanted intracerebral electrodes connected to a neurostimulator (implanted in the chest wall) to interfere continuously (though reversibly) with the functions of neurons surrounding the electrodes. High-frequency stimulation has become the first-choice surgical alternative to the medical treatment of idiopathic Parkinson disease. Findings from long-term studies of treatment for Parkinson disease indicate that DBS is highly effective in reducing severe motor complications (mainly tremor), although the overall process of degeneration cannot be slowed down.20
Adverse effects. Wound infection after surgery or battery exchange, lead migration, and device-related infections are important surgical complications in DBS. Lead migration (2.5% of patients), erosion, and infection (4.5% to 8.9% of patients) have been reported.21,22 So far, there is only one report of hemorrhage, although statistically, DBS surgery has a substantial risk (0.9%) for hemorrhage.23
Adverse effects (eg, erythema, increased anxiety, agitation, elevation of mood) of stimulation are typically transient and occur within minutes to hours after new treatment parameters have been introduced. The exact mechanism leading to adverse effects is not fully understood; however, in some cases (eg, oculomotor adverse effects), a modulation of neighboring neuronal tissue to the target region may explain the effect. If adverse effects persist and are judged to be troublesome, a change in stimulation settings is required.
Dr Conway is Associate Professor of Psychiatry at Washington University in St Louis. Dr Cristancho is Assistant Professor of Psychiatry at Washington University. Dr Schlaepfer is Vice Chair and Professor of Psychiatry and Psychotherapy at University Hospital Bonn, Dean of Medical Education at the University of Bonn in Germany, and Associate Professor of Psychiatry and Mental Health at The Johns Hopkins University School of Medicine in Baltimore. The authors report no conflicts of interest concerning the subject matter of this article.
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