In the past 15 years, there have been considerable advances in the research on and clinical use of neurostimulation for psychiatric disorders, especially mood disorders and MDD. These treatments offer hope to many, especially to patients with treatment-resistant disorders or those who cannot tolerate medication regimens. Current understanding of the optimal treatment methods, mechanism of action, and delivery of these treatments is evolving.
Three of the most recognized—repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS)—are reviewed in this article. An experimental new treatment—trigeminal nerve stimulation—is also briefly discussed.
Transcranial magnetic stimulation
Treatment overview. rTMS was the first noninvasive brain stimulation technique to receive FDA approval for the treatment of MDD. rTMS is typically delivered using an insulated magnetic coil placed on the scalp over the left dorsolateral prefrontal cortex. The coil induces a strong magnetic field (1.5 to 2.0 Tesla) that passes unimpeded through the skull into the brain and causes neuronal depolarization in a cortical area of approximately 2 to 3 cm2 and 2 cm in depth.1 Although depolarization is limited to the cortex, the stimulation is thought to exert its effects in more distant but functionally connected brain regions.2 rTMS is delivered in an outpatient setting, and a typical rTMS course delivers 3000 high-frequency (10 Hz) magnetic pulses 5 days a week for 4 to 6 weeks. Treatments are typically well tolerated; headaches and discomfort at the stimulation site are the most common adverse effects and the incidence of seizures is rare.
There have been more than 30 randomized controlled rTMS trials involving patients with MDD. Two large, multicenter, randomized controlled trials have shown superior antidepressant efficacy of rTMS over sham rTMS.3,4 In the study by O’Reardon and colleagues,3 rTMS antidepressant response rates were twice those of sham stimulation (23% response and 15% remission versus 12% and 5.5%, respectively, for sham after 6 weeks). A subsequent subanalysis of the trial concluded that the antidepressant effects were greater in MDD patients with less medication resistance, which led the FDA to approve rTMS for patients in whom only one antidepressant trial has failed.
Optimization strategies. Since the FDA approval in 2008, there has been a considerable increase in the use of rTMS for MDD throughout the United States. However, similar to the reimbursement situation with VNS and despite FDA approval of rTMS, most health insurance plans do not cover rTMS treatment. Medicare coverage appears to depend on local coverage determination. Recently, a few private insurance carriers have started to include guidelines for TMS coverage and approval is granted on a case-by-case basis.5
rTMS was used as an adjunct to medications in a study that comprised 100 patients with treatment-resistant major depression (TRMD).6 Response and remission rates were 50.7% and 24.7%, respectively, following up to 30 TMS treatments. The higher response and remission rates observed in this clinical trial were attributed to the higher rTMS doses used and the addition of concomitant low-frequency TMS applied over the right dorsolateral prefrontal cortex in select cases. The additive effects of coexisting medications were also thought to potentially account for the superior clinical response rates.
In recent years, several strategies have been used to optimize rTMS efficacy. These include high-dosing protocols that deliver up to 10,000 daily pulses; right-sided, low-frequency pulsing (1 Hz); and bilateral rTMS.6
Findings from 2 large meta-analyses indicate that low-frequency rTMS, which is believed to inhibit cortical activity in the underlying right dorsolateral prefrontal cortex, is efficacious in reducing symptoms of MDD. Schutter7 (N = 252) calculated an effect size of 0.63 for low-frequency, right-sided rTMS compared with sham. Berlim and colleagues8 (N = 263) estimated that approximately 30% to 40% of patients with MDD who received low-frequency rTMS were responders or remitters compared with 10% of those who received sham rTMS. Both meta-analyses concluded that the efficacy of slow, right-sided stimulation is similar to that of high-frequency left-sided stimulation. Hence, this treatment modality could potentially be used as an alternative to or in addition to left-sided rTMS. Furthermore, clinical advantages to low-frequency TMS include better tolerability with fewer reports of headache and significantly fewer seizures.9
Bilateral rTMS has also been proposed as a treatment optimization strategy. This approach combines sequential application of high-frequency left-sided stimulation with low-frequency right-sided rTMS. This approach is thought to produce synergistic effects, thereby maximizing treatment response. However, despite promising results from a randomized controlled trial that demonstrated greater response (44%) and remission (36%) with bilateral rTMS than with sham, a recent study found no significant differences between unilateral stimulation and bilateral rTMS.10,11 Note that these rTMS treatment optimization strategies remain off-label.
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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