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Severe depression is sometimes called “refractory” by doctors, meaning that it defies their efforts to combat it through a variety of means. These range from antidepressant pharmaceuticals to, in the most pronounced cases, the application of electrical impulses, either directly or indirectly, to areas of the brain believed to be important in depression.

NARSAD grants have energized the work of hundreds of scientists in a decades-long quest for safer and more effective treatments for refractory depression. Sometimes, NARSAD grants have proven critical to the early advancement of scientific discoveries that otherwise might have foundered. For Mark George, M.D., NARSAD’s aid helped him salvage a promising technology that others in the field were giving up on. Today, that technology, called rTMS, is a powerful non-invasive therapy for treatment-resistant depression.

During a research fellowship in London in 1990-91, Dr. George learned of a new technique called transcranial magnetic stimulation (TMS), then being used to study the brain’s motor cortex. In TMS, a focused magnetic field painlessly enters the brain and generates electrical
currents inside specifically targeted brain cells, or neurons. During this stimulation, TMS blocks brain functioning for brief periods in the targeted area.

Joining the National Institute of Mental Health after his fellowship, Dr. George pioneered TMS, first as a way to study the role of neurons in regulating mood. Later, he tested it as a non-invasive therapy, first in a single depressed patient, and subsequently in a double-blind clinical trial. That trial gave the exciting result that daily magnetic stimulation of the prefrontal cortex over a treatment period of three weeks significantly alleviated depression in some patients. The treatment became known as repetitive TMS (rTMS).

Dr. George moved in 1995 to the Medical University of South Carolina — where he is now Distinguished Professor of Psychiatry, Radiology, and Neuroscience — at a time when the bright hope of rTMS as an antidepressant was dimming if not dying. One team of researchers had reported remarkable success in lifting depression in patients by treating them with rTMS for only one week. “I didn’t understand then, and I don’t understand now, how they got those results,” Dr. George says. “Researchers around the world followed up by treating patients for one week, but none of them got better. The word spread: repetitive TMS doesn’t work.”

It was at this point that Dr. George sought federal and private support for a study to further demonstrate the effectiveness of rTMS. Only NARSAD responded. A Young Investigator Award enabled him to replicate his earlier NIMH clinical trial findings. “The NARSAD trial was important at a time when people were being skeptical about repetitive TMS,” he says.

Since then, Dr. George and others have improved rTMS and gained a better understanding of it. They’ve found, for example, that the success of rTMS depends on the degree of treatment resistance, not the severity of a patient’s depression. People who have failed one to three
medications often improve with TMS, while patients who had no improvement from seven or ten treatments do not. For these patients, electroconvulsive therapy, or ECT, remains the best hope. However, much remains to be resolved about rTMS, including where best to focus the magnetic waves.

“I credit NARSAD grants as extremely crucial for the development of repetitive TMS as an antidepressant,” Dr. George says. “It has supported me and others around the world in moving this technology from an idea to something I think will soon become an important mainstay of clinical practice.”

_{Mark S. George, M.D.}

FDA Approves TMS for Treatment of Depression

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