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Unlocking a Window: TMS for Refractory Depression

Distinguished Professor, Department of Psychiatry, Radiology, and Neurology, Director, Center for Advanced Imaging Research, Director, Brain Stimulation Laboratory, Neuroscience Institute, Medical University of South Carolina

This interview was conducted by Peter Cook on May 8, 2006.


Dr. Mark George first got the idea of using transcranial magnetic stimulation (TMS) to treat depression in 1990. He was working at the Institute of Neurology, Queen Square, in London, where doctors were using TMS to examine the motor system. “I had been doing brain imaging, trying to figure out what parts of the brain are involved in mood regulation,” Dr. George says. “When I first saw TMS being used I immediately said: what happens if you use it to stimulate some of the brain areas I’ve identified as being involved in depression?” It was some time before Dr. George got his chance.

Early Resistance to TMS for Depression

“When I first started toying with the idea of using TMS to target brain centers involved in mood regulation, specifically the prefrontal cortex, there were a number of significant obstacles to performing any kind of study,” Dr. George says. “With only a few exceptions, people weren’t thinking of depression as a regional brain disorder. Everyone had this ‘brain as soup’ idea. Also, the only successful physical treatment was ECT; the seizure was sacred, and no one believed that any brain stimulation that didn’t induce a seizure could have a positive antidepressant effect.”

In addition to those sizable impediments, there were also the standard safety concerns that attend any new treatment. Before Dr. George could perform clinical trials at the NIH, he first had to satisfy the IRB that TMS could actually influence activity in the prefrontal cortex and mood regulating systems. He conducted a trial on healthy controls, and although very little change in mood was produced, the study did demonstrate that TMS affected peripheral thyroid measures. “It became obvious that stimulating the cortex was somehow sending signals to the hypothalamus. And that meant that it could have an effect on mood regulation,” Dr. George explains.

Developing the Treatment

With the go ahead to start clinical trials, it was necessary to make a number of critical decisions. “There are a great many variables when you’re designing a new treatment,” Dr. George says. “We had to decide what areas to target, what intensity of stimulation to use, and the dosing paradigms. Our preliminary decisions were just educated guesses, but they’ve fairly consistently shown clinical antidepressant effects.”

To determine the dosing regimen, he contacted a number of doctors who were experts in ECT; they told him that they would have dosed every day if not for the side effects associated with overexposure to ECT. With no such side effects evident for TMS, Dr. George chose to dose Monday through Friday, leaving the weekend free merely for reasons of delivery logistics. As for the intensity of stimulation, Dr. George settled on the same voltage required to activate a motor response.

“It’s possible, behaviorally, to identify the place on the scalp and the intensity of stimulation required to move the contralateral thumb,” he explains. “According to standard models of the brain, the middle of the prefrontal cortex is about 5 cm forward from that point, so that’s where we decided to stimulate in the depression trials.” It’s since been shown that, in certain patients, generally those with larger heads, 5 cm isn’t enough to reach the prefrontal cortex, and results in targeting the premotor cortex. Newer studies make use of imaging techniques to customize the site of the stimulus to each individual patient. Dr. George believes that treatment must be continued for at least 3–4 weeks before positive results are experienced.

Clinical Trials

“There have now been 26 randomized, controlled trials of TMS for treating depression,” Dr. George says. “Many of them have shown TMS to be quite successful, but none of them have been multi-site, and the largest have only included 100 people. People are still tentative, because the medical community is used to seeing multi-site trials of 2–3 hundred people when evaluating new antidepressant treatments.”

Dr. George has recently begun one such study, as the NIH is funding a 4-site trial including 240 patients. Aside from enhanced trial-power, Dr. George is excited because “We’re getting brain images of every single patient in the study. When we get our results back, not only will we have a pretty good idea of how effective TMS is, but the data may tell us whether different target areas in the prefrontal cortex are preferred.”


“Regardless of how successful it proves to be,” Dr. George says, “I don’t think TMS will replace pharmacotherapy. It’s much easier to take a pill each day than it is to go into the doctor’s office for a TMS session.”

However, he believes that TMS could have demonstrable efficacy for patients with refractory depression. It’s been compared to ECT in 4 trials and was shown to be as successful as ECT in each of them. This was a surprise to Dr. George, who doesn’t believe that TMS has yet been applied in anything near the most effective manner.

“ECT is our most proven depression treatment. However, it’s expensive and complicated, and can cause memory loss in some patients.” Dr. George believes that, if proven effective in large trials, TMS could be a better choice than ECT for many and perhaps most treatment-refractory patients. “You don’t need an anesthesiologist, so it’s much cheaper, and no significant adverse effects have yet been discovered,” he says.

More research will be needed to show how TMS stacks up against two recent additions to the arsenal of brain stimulation techniques: vagus nerve stimulation (VNS) and deep brain stimulation (DBS), but it is, without a doubt, the least invasive form of brain stimulation. (Incidentally, Dr. George also oversaw the first ever depressed patient implanted with VNS as a potential treatment).


TMS has come a long way from when Dr. George first proposed it. “I was actually asked to leave one of the early ECT meetings,” he says with a laugh. “But now, people accept that depression is a brain illness and that it involves pathological changes in certain regions. It’s accepted that it’s not necessary to induce a seizure to treat depression; both DBS and VNS, which do not cause seizures, work as an antidepressant in some people.”

Dr. George predicts that TMS will be on the market and FDA approved within a year’s time. From there, it will take time to figure out the place of TMS in treatment algorithms, but if it is as successful as Dr. George believes it can be, TMS will be a part of depression treatment for many years to come.

Disclosure: Dr. George is a consultant for Aventis, Jazz , and Argolyn; is on the speaker’s bureau of GlaxoSmithKline and Parke Davis; has received research grants from Cephos, Cyberonics, DarPharma, Eli Lilly, GlaxoSmithKline, Janssen, and Neuronetics; and serves on the advisory board of Cephos, Cyberonics, and NeuroPace.

Source: www.neuronetics.com