When we last reviewed neurostimulation devices 3 years ago, we concluded that there was some promise—but more sizzle than beef. Now there are more devices and more data. But is there more beef? Maybe.

We generally think of neurostimulation as a new technology, but its history is long. Beginning in the 1870s and through the turn of the last century, electrotherapy, adopted enthusiastically in the U.S. and Europe after its introduction by German pioneers, became standard treatment for melancholia, neurasthenia, and related conditions. The most commonly used instruments were, in fact, substantially similar to those used today in transcranial direct current stimulation (tDCS). In light of current debates about the extent of the placebo effect in brain devices, it seems instructive that over 130 years ago, internationally recognized experts convened a symposium to debate the following question: “Are the positive results produced by electrotherapy based on suggestion?” Concerns about observer bias, the absence of a clear explanatory model, and the fact that electrical treatments were “repeatedly suspected of attaining results through suggestion only” led to their eventual fall from favor. By the early 1900s, in fact, electrotherapy had essentially disappeared from mainstream practice.

Thus cautioned, let’s sally forth into today’s therapeutic “electro-landscape.” We’ll restrict our focus to the treatment of depression, and specifically (where data are available) to treatment-resistant depression (TRD). Up for your consideration are: transcranial magnetic stimulation (TMS); magnetic seizure therapy (MST); vagus nerve stimulation (VNS); transcutaneous vagal nerve stimulation (t-VNS); transcranial direct current stimulation (tDCS); and deep brain stimulation (DBS).

Transcranial Magnetic Stimulation (TMS)
What is it? Transcranial magnetic stimulation (TMS) is a non-invasive procedure that uses magnetic fields to stimulate nerve cells in the brain. The magnetic coils look different depending on the device used. In the Neuronetics device, the patient reclines in what looks like a dentist chair and a coil is lowered onto the scalp near the forehead. In the Brainsway device, the patient sits in a standard chair and the device is more like a helmet that is put over the entire head. Standard treatments occur once a weekday for six weeks.

How available is it for patients? Many psychiatrists are offering TMS therapy to patients; it is available in most areas.

Does it work? In 2008, the FDA approved rTMS as a treatment for adults with MDD who “have not responded to a single antidepressant medication in the current episode.” As recently as early 2014 (Cusin C, Dougherty D, Biol Mood Anxiety Disord 2012;2(1):14), meta-analyses generally emphasized the paucity of well-designed trials and the often less-than-overwhelming results. For instance, the one large NIMH-sponsored, randomized, sham-controlled study “showed a statistically significant difference between the treatments, but overall low rates for both response and remission.” According to authors Cusin and Dougherty: “Based on published data, the role for TMS in the treatment of TRD is still unclear.”

Earlier this year, however, a team at Chapel Hill published the results of a meta-analysis of rTMS in a more narrowly defined population: “patients with major depressive disorder and 2 or more prior antidepressant treatment failures” (Gaynes B et al, J Clin Psychiatry 2014;75(5):477–489). They limited their data to “good- or fair-quality studies comparing rTMS with a sham-controlled treatment in TRD patients... published from January 1, 1980, through March 20, 2013.” Their results were distinctly more encouraging: “rTMS was beneficial compared with sham for all outcomes... produced a greater decrease in depressive severity (high strength of evidence), and greater response rates (high strength of evidence)… finally, rTMS was more likely to produce remission (moderate strength of evidence); patients receiving rTMS were more than 5 times as likely to achieve remission as those receiving sham (relative risk = 5.07; 95% CI, 2.50 to 10.30).”

Conclusion: For carefully diagnosed cases of TRD, it appears reasonable to consider rTMS.

Magnetic Seizure Therapy (MST)
What is it? The patient sits (or lies) in a reclining chair. Small magnetic coils are housed in two round pads attached to a pole that comes out of the main body of the machine. The pads are placed on either side of the scalp, just behind the temples. The operator activates the device and electricity is pulsed into the magnetic coils housed inside the pads. It is similar to the TMS pulse, but the pulses are at a higher intensity and frequency so that they produce a seizure. The patient is under general anesthesia for the procedure. This process directly stimulates the portion of the brain that regulates mood. MST resembles ECT in the number and scheduling of treatments (typically 2–3 per week for 4 to 6 weeks) and the need for anesthesia.

Proponents claim that, compared with conventional ECT, MST can produce a more precise cortical seizure focus. This would have a few advantages. First, it would eliminate the need for the bite block used in ECT because the masseter (jaw muscle) would not be stimulated. Second, and more importantly, the stimulus would not reach brain structures important for memory, such as the hippocampus. This would lead to less acute post-ictal confusion, faster recovery times, and a lower risk of cognitive and memory impairment, the chief bugaboos associated with ECT.

How available is it for patients? Not FDA approved; it is available to patients with major depression only through a research protocol.

Does it work? Since 2006, a handful of studies have, with a fair degree of consistency, shown MST to be effective for TRD. A non-industry funded review published earlier this year (Cretaz et al, Neural Plast 2015;Epub May 13) describes response rates ranging from 40% to 60% and remission rates ranging from 15% to 30%. The authors were impressed that “most trials were conducted on patients suffering from TRD, who had failed previous therapeutic strategies and therefore had a worse prognosis.”

They also found that MST does indeed cause fewer cognitive side effects than ECT—for example, the reorientation time was 2–8 minutes for MST vs. 15–25 minutes for ECT. In addition, MST is much less likely to cause prolonged memory loss. The downside is that MST, while effective, is quite a bit less effective than ECT for TRD. ECT posts remission rates of 50%-70%, at least double the reported remission rates from MST. The authors suggest that MST will gradually become more effective with improvements in lead placement, pulse frequencies, and other parameters.

Conclusion: It’s not clear how MST fits into the range of treatments available. It causes fewer side effects than ECT, but it’s less effective. And it may not be any more effective than TMS—which is a much less noxious procedure.

Vagus Nerve Stimulation (VNS)
What is it? Vagus nerve stimulation is a neurosurgical procedure. The patient is put under anesthesia, and the surgeon embeds a silver dollar-shaped device—the stimulator—under the skin of the upper chest, just below the collarbone. A second incision is made on the lower left side of the neck where three small electrodes are wrapped around the vagus nerve. The stimulator in the chest sends electrical impulses to the vagus nerve. The frequency and intensity of impulses can be adjusted non-invasively using a wand that interacts with the device remotely.

How available is it for patients? Though FDA approved, it is not widely available.

Does it work? Based on what many felt was lukewarm evidence (see for example TCPR’s 2006 update), VNS was approved by the FDA in 2005 for treatment-resistant depression. Its invasive nature; potential for messy mechanical problems (for example, any time a battery malfunctions); and side effects (including cough, hoarseness, sore throat, and headache) have resulted in very limited clinical use. One recent review (Cusin C, Dougherty D, Biol Mood Anxiety Disord 2012;2(1):14) was a little more bullish, concluding that while the device is not effective for acute treatment of depression, its effect seems to increase over time. In an open-label extension, patients given VNS were followed and had one-year response rates of up to 34% and remission rates of 15%. But there was no control group for comparison.

Conclusion: VNS is almost certainly ineffective for the first 3 months after implantation, but may become effective over time. We need to see more studies to be sure.

Transcutaneous Vagal Nerve Stimulation (tVNS)
What is it? tVNS is like VNS but without the need for surgery. A branch of the vagus nerve supplies a part of the ear, allowing you to stimulate the nerve with an electrode that is simply placed against the ear. In practice, the whole set looks like wearing headphones and listening to an iPhone. You just charge it up and wear the electrodes for the prescribed amount of time. 15 minutes once or twice a day for two weeks, and you have a potential treatment for depression.
How available is it for patients? It is approved in some European countries for the treatment of refractory epilepsy and can be prescribed there.

Does it work? A single pilot study randomly assigned 37 depressed patients to tVNS (worn for 15–30 minutes a day for two weeks) or to sham treatment. Active treatment beat sham on the Beck Depression Inventory but not the HAM-D scale. There were no side effects. (Hein E et al, J Neural Transm 2013:120(5):821–827).

Conclusion: tVNS has promise, but it’s much too soon to tell.

Transcranial Direct Current Stimulation (tDCS)
What is it? The device involves placing two electrodes—one at each temple—onto the patient’s head with an elastic band and flipping a switch. A relatively weak, direct (as opposed to alternating) electrical current is delivered for 20 to 30 minutes, 5 days a week, for 2 to 3 weeks.

How available is it for patients? No FDA approvals. Do it yourself kits are available to anyone. Other, more legitimate devices are available by prescription.

Does it work? At the time of our last review, the available evidence was discouraging: two blinded, sham-controlled studies showed modest symptom improvement, but no significant difference between treatment and control groups (for information, see this NIH page and this study). What’s happened since then?

As mentioned in this issue’s accompanying piece by Drs. Sahlem and Borckhardt (p. 8), a double-blind 2013 study randomized 120 subjects with MDD to active tDCS, sham tDCS, sertraline, or placebo. Active tDCS was better than sham, and the combination of sertraline and electricity was more effective than either treatment alone. Subsequent meta-analyses, however, have been mixed (of the three, one concluded that tDCS “has promise”; one found “a medium, significant effect size in outcomes”; and one euphemistically described the clinical utility of tDCS as “unclear when clinically relevant outcomes such as response and remission rates are considered”).

Conclusion: Larger studies still needed!

Deep Brain Stimulation (DBS) 
What is it? In this invasive form of treatment, electrodes are surgically implanted in deep brain structures, including the subgenual cingulate cortex (SCC; also known as Brodmann area 25, ref: Drevets et al, CNS Spectr 2008;3(8):663–681) and the ventral striatum/ventral cortex, that have been implicated in depression.

How available is it for patients? Available with proper consultation and assessment by doctors. This may require consults with multiple specialists, including psychiatrists, psychologists, neurologists, and neurosurgeons, to determine if the device is appropriate.

Does it work? After a series of very impressive open-label trials showing robust responses and few side effects, several large, multi-center randomized, sham-controlled studies were launched, accompanied by fanfare and great expectations. Disappointment has followed: At least two of these, one sponsored by Medtronic and the other by St. Jude Medical, have reportedly been shut down due to lack of measurable benefit in the treatment arms. According to one review author, “researchers involved remain hopeful that modifications of inclusion criteria and technique might ultimately result in a demonstrable clinical benefit for some subset of patients...” but for now, DBS remains an experimental form of treatment.

TCPR Verdict: 
Overall Verdict on Brain Stimulation for Depression
We have significantly more data now than we had just 3 years ago. And based on this evidence, the following conclusions seem reasonable.

• rTMS is effective for depressed patients who have failed one or more trials of an antidepressant.


• MST may have similar efficacy as rTMS.


• VNS, tVNS, tDCS, and DBS are interesting, but it’s still too soon to tell.