TMS initially was examined in several small, open-label studies that looked at various treatment parameters and stimulation sites. Several sham-controlled studies generally found TMS efficacious and further refined treatment administration. Its role in treating depression—and possibly other psychiatric disorders—has been supported by 2 recent meta-analyses.13,14
O’Reardon et al15 conducted the largest double-blind trial of active vs sham TMS (N=301) for moderately treatment-resistant major depression. This study began with a 4- to 6-week, blinded, randomized phase followed by 6 weeks of open-label TMS for initial nonresponders. The third phase reintroduced TMS over 6 months as needed to augment maintenance antidepressants. This trial utilized the most aggressive treatment parameters to date (ie, 10 Hz; 75 4-second trains; 26-second inter-train interval; 120% motor threshold) delivering 3,000 pulses per treatment over an average of 24 sessions. Compared with the sham procedure, patients who received active TMS showed significantly higher response rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) at weeks 4 and 6. Similar results were found for the 17- and 24-item HDRS. At 6 weeks, remission rate—defined as a MADRS score <10—was significantly higher in the active treatment group (14%) compared with the sham procedure (6%). A post-hoc analysis found that the most robust benefit occurred in patients with only 1 failed adequate antidepressant trial (effect size=0.83).16 This administration protocol was well tolerated, with no deaths or seizures and a low rate of discontinuation because of adverse events (5%).17 The most common adverse effects were application site pain or discomfort and headaches.
Recently, the second largest (N=190) sham-controlled trial of TMS for treatment-resistant major depression was published.18 This National Institute of Mental Health-sponsored, multiphase study included an initial 2-week, treatment-free period; 3 weeks of daily treatments over the left DLPFC using the same device and parameters as in the O’Reardon study; and an additional 3 weeks of treatment in patients who were improving. Those not responding to initial treatment were crossed over to open-label active TMS. This study advanced TMS development by:
- using a novel somatosensory system that produced similar sensations with sham and active TMS
- assessing the success of maintaining the blind
- establishing a rigorous clinical rating system
- utilizing MRI-guided adjustment of coil placement in a subset of patients.
The authors concluded that active TMS was significantly better than sham treatment in achieving remission (14% vs 5%). In addition, the raters, treaters, and patients were effectively blinded to the treatment condition. MRI-assisted coil placement found that in 33% of the sample, site placement determined by standardized assessment was over the premotor cortex rather than the prefrontal cortex, so the coil was moved 1 additional cm anteriorly in these patients. Similar to those observed by O’Reardon et al, adverse effects of active TMS were generally mild to moderate, did not differ by treatment condition, and led to a low discontinuation rate (5.5%).
Table 4
Treatment parameters of transcranial magnetic stimulation
| Parameter | Comment |
|---|---|
| Motor threshold | Lowest intensity over primary motor cortex to produce contraction of the first dorsal interosseous or abductor pollicis brevis muscle; visual or electromyographically monitored |
| Stimulus coil location | Most common: Left dorsolateral prefrontal cortex (DLPFC) Less common: Right DLPFC, vertex |
| Stimulus pulse(s) or train | |
| Intensity | 80% to 120% of MT |
| Frequency | ≤1 to 20 Hz |
| Duration | ≤1 millisecond |
| Interpulse interval | 50 to 100 milliseconds |
| Stimulus train duration | 3 to 6 seconds |
| Inter-train interval | 20 to 60 seconds |
| Source: Janicak PG, Krasuski J, Beedle D, et al. Transcranial magnetic stimulation for neuropsychiatric disorders. Psychiatr Times. 1999;16:56-63 | |
Deep brain stimulation
DBS is a “functional neurosurgical” procedure that delivers electrical current directly to specific areas within the brain.19 Its mechanism of action remains uncertain; depolarization blockade, synaptic inhibition, and “neural jamming” are leading hypotheses. In contrast to conventional ablative surgeries, DBS is reversible and adjustable. Implantation involves positioning pacemaker-like battery devices subcutaneously in the left and right upper chest. Electrodes attached to wires are run subcutaneously behind the ears and, with stereotactic guidance, placed through burr holes in the skull into specific CNS areas implicated in the pathophysiology of conditions such as Parkinson’s disease, refractory depression, and severe obsessive-compulsive disorder (OCD).
Antidepressant effects. The FDA recently approved DBS under its humanitarian device exemption program for intractable, severe, disabling OCD based on promising results from open and blind trials that stimulated areas such as the internal capsule and adjacent ventral striatum.20-22 These studies reported that DBS of the caudate nucleus for OCD and subthalamic nucleus for Parkinson’s disease also produced antidepressant effects. Subsequently, trials targeting the subgenual region (Brodmann’s area 25), the ventral capsule/ventral striatum, and nucleus accumbens demonstrated antidepressant effects.23-27 Pending the results of ongoing pilot trials, large, multi-center studies using different devices and target areas are being planned to clarify the role of DBS for patients with severe, disabling, refractory depression.