The future. The future for rTMS is promising. Technological advances in coil design allow stimulation of deeper brain structures—deep rTMS. Deep rTMS uses a special H coil that modulates cortical excitability up to 6 cm in depth. This allows for stimulation of the orbito-medial, cingulate, and insular cortical regions.
Although the number of treated patients is small, the preliminary results for deep rTMS for TRMD appear promising.12 In addition, the adverse effects of deep rTMS are similar to those of standard rTMS. Although rapid steps in technological advances and research are allowing for enhancement of TMS, a significant barrier to treatment is that the health insurance coverage remains low.
Vagus nerve stimulation
Treatment overview. VNS has been widely used in the United States and Europe for persistent treatmentrefractory seizure conditions. In 2005, the FDA approved VNS for TRMD.
A small electrical current is applied to the left vagus nerve using an implanted electrical generator (typically implanted in the chest region). The lead from the device is attached to the cervical region of the vagus. The patient receives around-the-clock stimulation, typically with stimulation periods, or “trains,” lasting 30 seconds, with 5 minutes of rest between trains. The electrical parameters (pulse width, frequency, duration of stimulation, and duty cycle) can be modified transcutaneously (as with cardiac pacemakers) using a “wand” that is attached to a small handheld programming computer. To date, there have been 5 large clinical trials that have shown the efficacy of VNS in TRMD.
Recent findings. Until recently, the optimal electrical treatment parameters for VNS in TRMD had not been studied. To clarify this issue, Aaronson and colleagues13 conducted a large, prospective, double-blind trial that used VNS applied at different electrical parameters. Patients with TRMD were randomized to 3 target stimulation settings: low (output current 0.25 mA, pulse width 130 microseconds); medium (0.5 to 1.0 mA, 250 microseconds); or high (1.25 to 1.5 mA, 250 microseconds). All treatment groups used the same duty cycles (30 seconds on and 5 minutes off) and pulse frequencies (20 Hz). The study was divided into a 22-week double-blind acute phase and a 28-week long-term phase. Unlike the acute phase, the long-term phase allowed dose titration.
Several relevant findings emerged from this study:
• There were no statistically significant differences in antidepressant efficacy among the 3 dosing groups in the acute, blinded phase (22 weeks)
• Statistically significant improvement in the primary measure of depression over the acute phase and long-term phase was seen in all 3 groups
• Continued antidepressant improvement was seen in all 3 groups in the long-term phase
The study demonstrated a relationship between the initial dosing and sustained antidepressant effect at the end of the long-term phase, ie, there was a statistically significant difference between the percentage of low-dose cohort responders (end of the acute phase) who maintained their response to the end of the long-term phase (44%) and the percentage of similarly sustained responders in the medium- and high-dose cohorts (88% and 82%, respectively). These findings suggest that higher-current dosing may be clinically superior to lower dosing in maintaining antidepressant benefits.
Understanding how VNS works. Clinical studies, as well as brain imaging studies, have demonstrated that the effects of VNS occur slowly. For example, in a 1-year extension of the pivotal trial of VNS in TRMD, the frequency of antidepressant response increased over many months of stimulation: 15% at 3 months, 18% at 6 months, 23% at 9 months, and 30% at 12 months.14 This cumulative increase in response in patients with TRMD closely tracks the response patterns observed in patients with epilepsy.15
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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