Severe Depression Responds To Low-Frequency Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a rapidly developing technique for the investigation of brain function and the treatment of neurological and psychiatric disorders. In the past decade it has gained increasing attention as a promising new therapeutic modality for treatment-resistant depression.

The major impetus for clinical investigation of rTMS is the need to find an effective somatic treatment but without ECT’s cognitive side effects for people who have depression and do not benefit from or tolerate existing therapies.

During rTMS treatment, pulsed magnetic fields are generated by rapidly switching on and off the electrical current in a small handheld magnetic stimulator held over the scalp of the prefrontal cortex. This depolarizes nerve cells with either stimulation or disruption of brain activity. Each TMS session lasts about 15 minutes and does not require an anesthetic or hospitalization.

Seizure Risk Greatest Concern

The greatest concern with the use of rTMS has been the possibility of inducing seizures. In early studies seizures occurred with high frequency stimulation (5-20Hz) to the left prefrontal cortex (HFL-TMS), but none occurred in later studies with low frequency stimulation (1Hz) to the right prefrontal cortex (LFR-TMS).

While known to be safer, the efficacy of LFR-TMS as a treatment for depression remained in doubt due to the unconvincing outcomes of several studies. And the efficacy of LFR-TMS as a treatment for depression had not been compared with that of HFL-TMS to determine its validity as an appropriate treatment.

Psychiatric News interviewed experts in this field in response to an important study headed by Paul B. Fitzgerald, M.B.B.S., of the Alfred Psychiatry Research Center at the Alfred and Monash University in Victoria, Australia.

For what is believed to be the first time, the study found that both HFL-TMS and LFR-TMS are effective for the treatment of medication-resistant major depression. Treatment for at least four weeks is necessary for clinically meaningful benefits to be achieved. In its report in the October 2003 Archives of General Psychiatry, the team concluded that treatment with LFR-TMS appears to be an appropriate initial rTMS strategy in depression, and it is safe, effective, and well tolerated by patients.

In the double-blind, randomized, sham-controlled trial, 60 patients who had failed to respond to treatment with multiple antidepressant medications were divided into three groups of 20 that did not differ in age, sex, or any clinical variables. All completed the trial.

The study included two treatment groups—one received 20 five-second HFL-TMS trains at 10 Hz, and the other received five 60-second LFR-TMS trains at 1 Hz. A third group received sham stimulation that was applied with the coil of the magnet angled 45 degrees from the scalp, resting on one wing of the side of the coil.

There was a significant difference in response among the three groups. A significant difference was seen between the HFL-TMS and sham groups and between the LFR-TMS and sham groups. There was no difference between the two treatment groups. Baseline psychomotor agitation indicated there was a successful response to treatment.

Low Frequency Reduces Seizure Risk

Fitzgerald told Psychiatric News that there are two clinically relevant points to take away from his study:

“First, our findings contribute to the base of evidence helping establish TMS as a genuine treatment alternative for this patient group. The second is in regard to low frequency, right-sided stimulation, which has not previously been shown to be effective in treatment-resistant depression.

“The importance is that low frequency stimulation has significant advantages over the more well-established high frequency, right-sided stimulation. Specifically, it is not only safer, since it reduces the likelihood of inducing seizures, but it is much better tolerated by patients, meaning they will be less likely to drop out of treatment.”

Fitzgerald believes there is now sufficient evidence of the safety and effectiveness of rTMS for it to be made more available to patients with treatment-resistant mood disorders, and it is appropriate for patients with treatment-resistant depression, as they have few treatment alternatives and experience significant suffering.

“If it is to be of clinical utility, it is likely to be best applied in treatment of nonresponsive patients. Safety studies of rTMS suggest it is associated with few problems, but it has been applied for such a short time that in clinical and research settings there remains the potential for the emergence of long-term safety issues, indicating the need for large-population studies and long periods of evaluation,” he said.

Commenting on the study, David Avery, M.D., a professor in the department of psychiatry and behavioral sciences at the University of Washington School of Medicine’s Harborview Medical Center in Seattle, said that most studies have used rTMS at frequencies of 5, 10, and 20 Hz, and relatively few studies with 1 Hz have shown effectiveness.

“In general the sample sizes in these studies have been small, so we don’t have a definitive answer as to whether 1 Hz gives as good a stimulation as higher frequencies. I think that his study certainly gives suggestive evidence that 1Hz is effective treatment. This shows promise, but we need more studies,” he told Psychiatric News.

Another issue raised by the report, according to Avery, is that a lot of meta-analyses of previous studies have shown statistical significance compared with sham treatment. He finds it interesting that studies with a great number of sessions, pulses, and higher intensity appear to have higher response rates. In early studies, investigators wanted to avoid potential side effects, such as seizures, so they started off with a fewer number of pulses, fewer number of sessions, and lower intensities.

Avery hopes that a multisite study proposed to the National Institute of Mental Health will be funded, because larger numbers of subjects need to be studied. Much will depend on the results of a multisite, industry-sponsored trial by the largest American TMS manufacturer, Neuronetics. The trial began last December and is expected to be completed within a year.

Study Methodology Sound

Mark George, M.D., who conducted both the first open and double-blind studies of rTMS for the treatment of depression, complimented the work of Fitzgerald’s team.

“This is a very well-done study and a convincing result showing that rTMS applied daily over the prefrontal cortex can treat depression,” he told Psychiatric News.

There have been almost 20 randomized controlled trials on rTMS, he said, but “this one is in the top of that group because of the sample size, the fastidiousness of its execution, and the fact that it was done by an independent scientist who really hasn’t published in this area,” said George, an associate professor of psychiatry, radiology, and neurology and director of the function imaging division for psychiatry at the Medical University of South Carolina in Charleston.

Asked for the rationale behind which side of the brain he chose to stimulate in his early studies, George said he picked the left side of the prefrontal cortex first because that’s where imaging studies have found more abnormalities in depressed patients. In a pilot study he found that stimulating the right side caused more pain, so he defaulted to the left side. He admitted that during much of the early work deciding what parts of the brain to stimulate was based on very little data and was mostly guesswork.

From Research to Clinic

How long it will be before research findings of rTMS are translated into clinical practice depends on the country in which the question is being asked. rTMS has been approved by the Medical Devices Bureau of the Canadian Health Ministry for specific applications. In some cities the treatment is being used regularly, according to George. Patients must be resistant to an adequate trial of antidepressants, must be between the ages of 18 and 64, and must meet APA guidelines for ECT.

Australia and New Zealand are expected to approve the treatment in the near future. The Australian Psychiatric Society issued a position paper recently in support of it as a clinical tool. And rTMS is widely used in Israel.

Applications for approval filed with the U.S. Food and Drug Administration (FDA) have not been granted to date. Technically rTMS can be done in the United States, and rTMS machines are manufactured here. Some American psychiatrists are using rTMS “off label” in their practices for treating other illnesses. Neuronetics hopes that the results of its multisite trial will lead to FDA approval for the company’s device.

“My reason for using high frequency then, and still is, is that when you stimulate the cortex, you are sending signals deeper down into the brain and in regions that are important in regulating mood,” said George. “We did one study where we looked at high frequency versus low frequency all on the left, and there was no difference. So my guess that high frequency was better may have been incorrect. Fitzgerald’s data suggest that low frequency, at least on the other side, is probably just as good. It likely is safer and to some degree less painful. The seizure risk is also lower.”

All sites and studies with rTMS have shown not equivalence but a lack of a difference with reasonable sample sizes, he continued. “So Fitzgerald is showing that the effects are likely in the same ballpark, but they haven’t shown from a scientific standpoint true equivalence. Nevertheless, they show that the effects of size that we get with rTMS are quite similar and suggest that as rTMS matures and develops as a treatment option, it may be something that one would use prior to giving someone conventional ECT because it’s less risky.”

He said he is somewhat disappointed that other investigators and clinicians seem to have continued to do rTMS according to his original work, giving it once a day every day. He believes it may be possible to give it every other day, but no one has studied that schedule.

“Maybe we could give it in ways that are more palatable, but that’s all work that needs to be done,” he said.

An abstract of the study, “Transcranial Magnetic Stimulation in the Treatment of Depression: A Double-Blind, Placebo-Controlled Trial,” is posted online at http://archpsyc.ama-assn.org/cgi/content/abstract/60/10/1002. Additional information on the Neuronetics’ multisite trials can be accessed at www.neuronetics.com/Main.html by clicking on “Clinical Trials.” ▪

Arch Gen Psychiatry 2004 60 1002