In recent weeks, researchers led by two BBRF grantees have reported encouraging results of a small pilot trial comparing the clinical and cognitive effects of electroconvulsive therapy (ECT) vs. magnetic seizure therapy (MST) in patients experiencing an episode of bipolar depression.
Separately, the same investigators and colleagues reported results of a much larger trial confirming MST’s “non-inferiority” vs. ECT in treating major depressive disorder (MDD), again with a notable safety advantage. (Results of this depression trial are discussed at the end of this article.)
Depression in bipolar disorder (BD) is sometimes regarded as more difficult to treat than “unipolar” depression, i.e., MDD. Like those with MDD, patients diagnosed with BD have had one or more episodes of major depression (dangerously low mood); but they also have had one or more episodes of mania or hypomania (dangerously elevated mood). Depressive episodes account for an estimated 75% of illness in BD patients, and their depression is often resistant to treatment.
In the newly reported pilot trial for depression in bipolar disorder, a team led by Daniel M. Blumberger, M.D., of the Centre for Addiction and Mental Health in Toronto, a 2010 BBRF Young Investigator, and Zafris J. Daskalakis, M.D., a 3-time BBRF grantee and member of the BBRF Scientific Council at the University of California, San Diego, address the question of how ECT and MST compare in terms of impact on bipolar depression symptoms and an array of cognitive measures. These questions have rarely been studied in bipolar depression.
ECT has evolved significantly in recent years. It briefly applies electricity directly to the brain via electrodes placed on the scalp. This induces a brief seizure in the brain which can have rapid and enduring therapeutic benefits not only for severe depression but other illnesses including psychosis. The treatment is administered painlessly while the patient is under anesthesia. ECT is well known to be highly effective in depression: significant reductions in symptoms are typically achieved in two-thirds to three-fourths of patients, usually within the 4 weeks of a full treatment course. But ECT is underutilized relative to other treatments, even ones likely to be less effective. This is because of its impact on memory: some degree of impairment frequently follows treatments for a period of time, before, in many cases, resolving or lessening.
BBRF Scientific Council member and 4-time grantee Sarah H. Lisanby, M.D., has led teams that worked to develop MST, in which magnetic fields, rather than electricity, are used to induce a therapeutic seizure in patients. As in ECT, the patient receives the treatment painlessly while under anesthesia. But the strength of the stimulation applied to neural circuits is less than in ECT, and is also more focused in the brain. Dr Lisanby and colleagues have shown that in patients with major depression, MST is “noninferior” to ECT in reducing depression symptoms, but does not impair memory as much as ECT sometimes does.
Drs. Blumberger, Daskalakis and colleagues wanted to find out if this was also true in patients in the depressive phase of bipolar disorder. A group of 55 patients was recruited for their double-blinded trial, 27 of whom were randomly assigned to receive ECT and 28 to receive MST. A relatively new approach to delivering ECT was used, called RUL-UB (right unilateral ultra-brief pulse), in which one electrode is placed on the right temple and the other is placed near the top of the head; the electrical pulses delivered are extremely brief, less than half a millisecond. This form of ECT was developed with the explicit intention of reducing memory-related side effects.
The electrical field induced by MST is 5 to 10 times more focused than that induced by RUL-UB ECT. This “spares medial temporal brain structures thought to be involved in the cognitive adverse side effects of ECT,” the team notes in its paper, which appeared in The American Journal of Psychiatry.
Of those initially recruited for the pilot trial, 35 had bipolar I disorder and 20 bipolar II. Most were in their early 40s and White, and 33 were female. 80%-90% were assessed to be either “markedly ill” or “severely ill”; about half had been in their current depressive phase for a year or less, the remainder for longer.
The participants were treated until they achieved remission from bipolar depression symptoms, dropped out, or received a maximum of 21 treatments.
The main results were these: MST had “similar clinical effects on [bipolar] depression symptoms relative to ECT,” with “a greater proportion of individuals in the ECT group experiencing worsening performance” on a test of autobiographical memory, which was one of several components of cognitive assessment in the trial. The others included measures of global cognitive function, intellectual abilities, attention, processing speed, verbal fluency, anterograde memory (ability to create new memories) and retrograde memory (recall of past memories), and executive functions.
Of the 45 participants whose data could be used for analysis, 6 of 20 (30%) in the ECT group and 5 of 25 (20%) in the MST group achieved remission of depression. Clinically significant worsening of autobiographical memory (a 25% decline or greater in score) occurred in 6 of 22 ECT recipients (22%) vs. only 2 of 28 (7%) in the MST group.
Other important assessments: the time it took to “reorient” following ECT treatments was 19 minutes, compared with 7 minutes for MST. Both treatment types reduced suicidal ideation—something already well established for ECT, and important therefore to test in MST. There were four serious adverse events reported during the trial, all within the ECT group; also, more participants dropped out early from the ECT group.
Effectiveness of both treatment types in this trial was a bit less than recorded in some past trials, which the team thinks may be related to specific clinical and demographic factors in the cohort, among these a younger average age than in some other trials and a higher rate of participants with treatment-resistant depression. The team noted that “patients with a strong preference for MST often declined participation in the trial because of the risk [in the trial setting] of potentially being assigned to receive ECT.” In general, the researchers believe their results may be widely applicable especially to those patients “with complex, difficult-to-treat illness who decline or are reluctant to consider a course of ECT—a potentially very large group of patients.”
While this pilot trial was too small to statistically demonstrate the “noninferiority” of MST vs. ECT using remission as the primary outcome, the team said that their findings, while “preliminary” due to the small trial size, showed that “MST is a promising treatment for the depressive phase of bipolar disorder that has not responded to first-line treatment.”
“While MST may yield somewhat lower remission rates, the cognitive safety profile is a major factor that can impact patient and provider decision-making.” The researchers called for additional research studying more patients, as well as continuing research dedicated to improve the efficacy of both ECT and MST.
In the most recent issue of Lancet Psychiatry, many members of the same team, led by Drs. Blumberger, and Daskalakis, reported results of a much larger clinical trial (called CREST-MST) comparing RUL-UB ECT vs. MST, this time in patients with unipolar depression, i.e., major depressive disorder. It is the largest randomized trial of convulsive therapy yet conducted, involving 239 patients across three academic centers in Canada and the U.S.
Results showed that in statistical terms MST, as prior smaller trials indicated, is indeed “non-inferior” to RUL-UB ECT in treating major depression, generating a remission rate of 22.5% (vs. 27.8% for the ECT treatments). Importantly, MST was significantly superior in terms of cognitive safety: only 2.7% of MST patients had clinically meaningful worsening on an autobiographical memory test vs. 17.3% in the ECT group. As Dr. Daskalakis notes, MST also outperformed ECT on measures of global cognition, verbal learning, verbal fluency, executive function, time to reorientation, and subjective cognitive complaints; and it proved non-inferior to ECT in remission of suicidal ideation.
“Our interpretation in this paper,” he said, “is that the overall risk–benefit profile supports MST as a first-line convulsive therapy in MDD, particularly for the substantial population of patients who refuse ECT due to cognitive concerns.”
Shawn M. McClintock, Ph.D., 2008 BBRF Young Investigator, was involved in both trials. The CREST-MST trial for depression also included Carol A. Tamminga, M.D., a BBRF Scientific Council member, 2011 Leiber Prize winner and 2-time Distinguished Investigator, and Cory R. Weissman, M.D., 2021 BBRF Young Investigator.