About 40% of patients with treatment-resistant major depression achieved remission in a randomized trial of repetitive transcranial magnetic stimulation (rTMS) — but the rate was virtually the same with sham treatment versus active stimulation, researchers said.
Among 81 patients in Veterans Affairs medical centers assigned to active rTMS, 33 (40.7%) achieved remission at the end of treatment, compared with 31 of 83 (37.4%) receiving sham treatment, reported Jerome Yesavage, MD, of Stanford University School of Medicine, and colleagues in JAMA Psychiatry.
After a 24-week follow-up phase, 16 out of the 81 receiving active treatment (19.8%) remained in remission while 13 (15.7%) of the sham did.
“On the surface it’s puzzling why the active would not be better than the sham and why both groups showed such a high resistance rate,” Charles Nemeroff, MD, PhD, of the University of Miami, who wrote an editorial accompanying the study, told MedPage Today. Most other rTMS studies have shown benefit, though not always large, relative to control.
“When patients are enrolled in clinical trials and they get a great deal of attention from healthcare providers,” Nemeroff said, “there’s a therapeutic effect that I think would explain to some extent the higher rate of remission in the sham treatment.”
Indeed, strong placebo responses and spontaneous remission with no treatment are common in major depression, as the FDA noted in a recent update to its guidance on antidepressant trials.
Treatment options for patients with treatment-resistant major depression are limited and typically invasive in nature, using monoamine oxidase inhibitors or electroconvulsive therapy. More recently, ketamine and derivative drugs have shown promise for rapid relief of severe depressive symptoms, but these have not been formally approved and are used clinically only in emergency situations.
Such methods may be necessary in suicidal patients, but for more moderate cases, researchers hypothesized that treatments such as rTMS could provide a less invasive solution, particularly in veterans, who often have multiple existing medical and psychiatric diagnosis that can reduce their response to treatments.
Previously, a similar sham-controlled study conducted by George Lisanby, MD, and colleagues (OPT-TMS) found that 14% of participants who received rTMS treatment successfully achieved remission, compared to 5% in the control group. Other studies in treatment-resistant depression, such as the landmark STAR*D trial, also found remission rates far lower than in the VA study.
In his editorial, Nemeroff said it was hard to explain the current trial’s high rates. But he noted that the VA population differs in several ways from patients in most depression studies, most notably that VA patients are mostly male, whereas traditional study samples are typically two-thirds female.
Yesavage and colleagues also pointed out that their treatment sessions were about twice as long as those in the OPT-TMS study.
The researchers said they hope, in the future, to target more concentrated areas of the brain and use different types of stimulation such as theta burst and TMS coil type, depending on biological differences in participants. Nemeroff said future studies might also include sampling for genetic markers or brain imaging to control for potential confounding variables.
To enter the trial, participants had to have failed at least two prior drug therapies and meet DSM-IV criteria for major depressive disorder. Patients with certain psychiatric comorbidities were excluded, but not all: 49.4% of the sample had post-traumatic stress disorder and patients with substance use disorder comprised 53.7%. Of the 40 patients with PTSD, 13 (32.5%) demonstrated remission, as did 13 patients in the sham (31.7%). No significant effects were seen at the end of acute or follow up phases across patients with PTSD, as well as across rates of suicidality and quality of life. Substance use disorder did not affect study results.
Of the 81 who received rTMS, 60 completed the treatment, nine discontinued treatment during the acute treatment phase, and 12 terminated during the follow-up phase, compared to 65 fully completing the treatment of the 83 in the control group, nine terminating during the acute stage, and nine withdrawing during follow-up. Subjects cited being lost to follow-up appointments, burden of visits, unable to return to clinic, adverse medical event, and withdrew from study as reasons for discontinuing their treatment. Other limitations included the small sample size and the fact that the study was conducted during 2012-2016, and hence newer rTMS protocols were not tested.
“It’s fabulous that VA leadership in research agreed that this was an important question in our depressed veterans,” Nemeroff told MedPage Today. “What we really want to know with a patient sitting in our office who’s depressed is, out of the myriad of treatments available, what is the best treatment for them. This is a very active avenue of investigation.”