TMS could still shift the psychiatric treatment paradigm, despite failure in VA trial

In June, we reported on a disappointing trial of transcranial magnetic stimulation (TMS) for treatment-resistant depression, which found no advantage for the treatment over a sham version in a Veterans Affairs (VA) population. In this follow-up article, we take a look at further developments in TMS since that story appeared.

Two experts offered different explanations for the mixed results of the VA trial, which appeared in JAMA Psychiatry and reported that among 164 patients from VA medical centers, 40.7% of those assigned to active repetitive TMS achieved remission at the end of treatment compared with 37.4% of those who received sham treatment (OR 1.16, 95% CI 0.59-2.26, P=0.67).

“This was a very complicated patient population in the VA system that included patients ranging from mildly to severely ill, many of whom had significant histories of PTSD and substance use,” Andrew Leuchter, MD, of the University of California Los Angeles (UCLA), told MedPage Today. “Most depression studies have not included such patients. The results therefore are difficult to interpret.”

Charles Nemeroff, MD, PhD, of the University of Miami, who authored an editorial that accompanied the study, offered another explanation for the findings.

“When patients are enrolled in clinical trials, and they get a great deal of attention from healthcare providers, there’s a therapeutic effect that I think would explain, to some extent, the higher rate of remission in the sham treatment,” Nemeroff told MedPage Today.

Updated Guidelines

After its initial approval in 2008, the FDA expanded the use of TMS in 2013 to include treating pain associated with certain migraine headaches. Within the past year, researchers have investigated how effective TMS is in treating other disorders such as anxiety, tinnitus, or other forms of chronic pain, said Leuchter, who heads the TMS Clinical and Research Program at UCLA.

In August, the FDA approved the use of TMS for obsessive compulsive disorder based primarily on the results of a multi-center randomized trial in which 38% of patients responded to the BrainsWay device compared with 11% of patients using a sham device. This follows the publication of new FDA guidelines in June, stating that because strong placebo responses and spontaneous remission with no treatment are common in major depression trials, placebo groups are necessary when studying new agents, especially in light of the increased usage of rapid-onset drugs, like ketamine, that are more frequently used to treat depression.

The FDA also approved a faster theta burst stimulation (TBS) technology, “ExpressTMS,” which involves sending magnetic stimulation at a higher frequency through the brain, and cuts treatment time from 37 minutes per session to just 3 minutes. The approval was based on the THREE-D trial, in which 33% of participants achieved remission from major depressive disorder and 50% had improved symptoms.

The Research

Leuchter said the approval of TBS made this type of treatment much more accessible and cost effective.

In his lab, he said he is currently working with a novel treatment, synchronized transcranial magnetic stimulation (sTMS), which matches the oscillations of the brain to the frequency at which it is being stimulated. Leuchter said he uses electroencephalograms while simultaneously stimulating the brain with magnets, so that he can study the electrical patterns of the brain induced by the stimulation. This can potentially allow researchers to direct more targeted TMS treatments by identifying certain biomarkers that pinpoint what the most effective settings are for each patient. For example, while the traditional frequency used for TMS treatment is 10 Hz, certain individuals respond better to fewer or more frequent pulses, Leuchter explained.

They also respond differently when different areas of the brain are targeted. In November, Leuchter co-authored a study investigating the efficacy of sTMS, which found that the novel treatment reduced depressive symptoms, and was more effective in patients with more severe depression and anxiety. Additionally, patients who had not had TMS treatment were more likely to respond to sham.

In another study, researchers found that when the orbitofrontal cortex, a generally poorly understood region of the brain, was stimulated, patients reported improvements in mood, although only if they had more severe symptoms at onset.

And a group of Italian researchers successfully targeted the cerebellum with TMS to improve motor functions in patients who had undergone an ischemic stroke. After 3 weeks of repetitive, intermittent theta-burst magnetic stimulation and paired physical therapy, patients had improved walking and balancing capabilities, according to the study.

What the Future Holds

TMS is being used more frequently and could be a potential avenue for treating several conditions including tinnitus, for which there are few treatments, or chronic pain, for which healthcare professionals are looking for alternative, non-pharmacological treatments in light of the opioid epidemic, Leuchter said. Some small trials have also demonstrated that stimulating the brain may improve Parkinson’s symptoms and memory loss.

One of the main challenges moving forward will be making TMS treatment more accessible for patients. Although TMS is indicated for treating depression in patients who have failed to benefit from at least one depression medication, these therapies are not typically covered by insurance. A single session may cost a patient upwards of $200. Additionally, the machines that perform the stimulation are large and may require patients to travel to a facility that owns the equipment in order to receive treatment.

The advantage of sTMS treatment is that the devices used to stimulate the brain are much smaller and worn as headsets, so they could potentially be taken home, which could be a “game changer,” Leuchter said.

“It’s a paradigm shift for psychiatry,” Leuchter said. “We’re very used to seeing patients in our office and prescribing medication or doing psychotherapy, but the idea of using a medical device to treat depression is still pretty novel, and it’s going to take a while to be fully adopted in the field. But I think it has a huge amount of promise.”