Building on past clinical trials demonstrating that magnetic seizure therapy (MST) is as effective as electroconvulsive therapy (ECT) in reducing the severity of symptoms in major depressive disorder, a newly published analysis of clinical trial data indicates that MST is also safer than ECT, specifically in terms of its impact on cognition.

In both ECT and MST, doctors intentionally induce a seizure in the brain, while the patient is under general anesthesia. In both forms of therapy, the seizure is induced by changes in electrical activity: in ECT, via electricity introduced directly into the brain by electrodes placed on the scalp; in MST, by electricity indirectly induced in the brain by sending magnetic pulses through the skull via an electromagnetic stimulator placed on the scalp.

ECT has been given, in various forms and with a range of side effects, for over 80 years. It is one of the most effective treatments for major depression ever tested, with over half of severely affected patients experiencing significant reductions in symptom severity or remission after a typical treatment course, which usually consists of 3 treatments weekly for 2-4 weeks. These effects can last for many months.

ECT’s side-effects profile has been greatly improved over the last 20 years. In the newly reported study comparing cognitive impacts of ECT and MST, the form of ECT that was used—called ultra-brief pulse right unilateral ECT—has been shown clinically to be associated with milder cognitive side effects than any other form of ECT. Still, even this most advanced application of ECT is associated with a range of cognitive effects, albeit significantly less pronounced than in other forms of ECT. Among these impacts, the most notable are short-term memory effects. While these side effects are often transient, usually fading within weeks or months, they suffice to dissuade many patients with severely symptomatic depression from ECT treatment.

With the hope of developing a non-invasive seizure therapy for major depression that has a better side-effects profile, Sarah H. Lisanby, M.D., has led research on MST for many years, having performed the first MST procedure in a patient with depression 25 years ago. Dr. Lisanby, a BBRF Scientific Council member, is Director of the Noninvasive Neuromodulation Unit, Experimental Therapeutics & Pathophysiology Branch, in the Intramural Research Program at the NIH. She is also Director at NIMH’s Division of Translational Research. Dr. Lisanby is the recipient of 3 BBRF grant awards, including a BBRF Distinguished Investigator Award (2010), and is a winner (2001) of the BBRF Klerman Prize for Exceptional Clinical Research.

Several recent randomized clinical trials comparing ECT and MST have found that they produce similar antidepressant effects and outcomes. This was a major hurdle for MST to pass, but these studies also suggested that MST generated fewer or less severe cognitive side effects. In their newly reported paper, Dr. Lisanby, with first author Shawn M. McClintock, Ph.D., of the University of Texas Southwestern Medical Center, and others, for the first time clinically compared MST with that form of ECT with the best cognitive side-effects profile, ultra-brief pulse right unilateral ECT. Dr. McClintock is a 2008 BBRF Young Investigator. Zhi-De Deng, Ph.D., a 2017 BBRF Young Investigator, was also on the team.

The study, reported in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, analyzed results of 73 participants with major depression, 35 of whom were randomly assigned to receive MST and 38 ECT. Participants, who, like those who treated them, were blinded as to which therapy they were receiving, had three MST or ECT sessions per week until they achieved remission or had a plateau in therapeutic response. Comprehensive neurocognitive tests were given to each participant before treatments began and 24 and 72 hours after they were completed. These tests assessed attention, autobiographical memory, executive function, learning and memory, motor function, processing speed, subjective cognitive function, verbal fluency, and working memory.

Like past trials, this one found the two therapies had similar—and major—antidepressant effects. But, the team reported, “there were vast differences in their neurocognitive effects.” Transient short-term amnesia for new information and for autobiographical memory recall and consistency are “hallmark difficulties observed with ECT, but not with MST,” they said.

In this trial, “following MST treatment, [participants had] significant improvement in fine motor dexterity, and no significant change in cognitive domains of attention, verbal fluency, executive function, or verbal learning and memory. In contrast, following treatment with ECT, patients demonstrated significantly worse performance on measures of verbal fluency, executive function, and verbal memory retention.” The study also indicated “stable autobiographical memory” following the MST course, “suggesting that MST had no adverse impact” on this form of memory.

Researchers have long wanted to know whether it is the seizure (in ECT or MST) or the accompanying alteration of electrical patterns in the brain that accounts for the clinical effects (antidepressant response and side effects). It might be both, but that remains uncertain. While the current study does not provide a definitive answer, the team did propose possible explanations for MST’s advantageous cognitive side-effects profile. The electrical field induced by ECT “is broad across the whole cerebral cortex with deep penetrance into both cortical and subcortical brain structures. ECT tends to also stimulate a greater amount of brain volume than MST.” The MST-induced electrical field “is confined to the superficial cerebral cortex, with little or no penetrance into cortical and subcortical brain structures,” the latter including areas crucial for learning and memory including the hippocampus and amygdala. This would support the hypothesis that the electric field drives cognitive side effects while the seizure drives efficacy.

There is more research to be done, the team urged. ECT’s unwanted cognitive side effects have been shown to reduce over a period of weeks and months; no such studies have yet been performed on individuals receiving MST or on how long the benefits of MST typically endure beyond the 6-month follow up reported in one of the team’s earlier papers. It is also important, they said, to replicate the current findings in considerably larger clinical trials that include neuroimaging information, and also to investigate whether and how differences in individual patients can affect the efficacy of MST.

The team believes that their study, in showing “the neurocognitive safety of MST," has "clinically meaningful and beneficial implications for clinical practice.” In addition to the lack of impact on memory, those who receive MST usually have a more rapid “reorientation [i.e., short-term recovery] time” following treatments, which “could lead to quicker recovery and discharge,” as well as “a quicker return to independence with activities of daily living (e.g., managing finances, driving) and functional responsibilities (e.g., employment, home management)” compared with patients treated with ECT.

They also suggested the value of testing MST in other conditions, including older adults with major depression and cognitive impairment and those with neurodegenerative disorders, as well as in adolescents with refractory major depression. It might also have a role in treating catatonia and in severe, treatment-resistant bipolar depression, they said.