Medscape Medical News
Deborah Brauser
August 07, 2024
For years, electroconvulsive therapy (ECT) has been a lifesaving treatment for patients with treatment-resistant depression (TRD), yet exactly how it works has largely remained a mystery. Now researchers believe they have uncovered the underlying mechanisms behind its therapeutic effects — a discovery that may help clinicians better predict treatment response in individual patients and quell much of the fear and stigma associated with one of psychiatry’s most effective, yet misunderstood, treatments.
Two recent papers published in Translational Psychiatry have highlighted the significance of aperiodic neural activity. The first study showed this activity increased following ECT treatment. The second study expanded on these data by demonstrating a significant increase in aperiodic activity after patients received either ECT or magnetic seizure therapy (MST), which has a better side-effect profile than ECT but lower efficacy.
Aperiodic activity is “like the brain’s background noise, and for years scientists treated it that way and didn’t pay much attention to it,” first author Sydney E. Smith, a PhD candidate at the Voytek Lab in the Neuroscience Graduate Program at the University of California San Diego (UCSD), said in a press release.
However, aperiodic activity boosts inhibitory activity in the brain, effectively slowing it down,” the investigators noted.
In an interview with Medscape Medical News, Smith used a car analogy to explain the mechanism behind ECT. “ECT might be increasing the activity levels in the brain cells that help calm it down. It taps on the brakes that tend to malfunction in depression. By restoring the balance between the gas and the brakes in the brain, some of those depressive symptoms are alleviated,” she said.
Smith added her team’s research helps demystify one of the most effective yet stigmatized treatments for severe depression.
“Aperiodic activity as a physiologically interpretable EEG metric could be a really valuable new predictive indicator for treatment response,” she added.
Fear and Stigma
ECT is primarily used for TRD and is effective in up to 80% of patients, yet it remains one of the least prescribed treatments.
Although it’s been around for almost 90 years, fear and concern about its potential cognitive side effects have contributed to its poor uptake. It is estimated that less than 1% of patients with TRD receive ECT.
Smith noted that the 1970s movie One Flew Over the Cuckoo’s Nest still contributes to ECT’s stigma. In the film, actor Jack Nicholson’s character is forced to undergo ECT as a punishment.
It’s important for clinicians to acknowledge the stigma while advising patients that “the actual treatment doesn’t look anything like what’s in the movies,” noted Smith. Patients must give informed consent for the procedure, and it’s delivered with the lowest level of effective stimulation.
“So many steps are taken to consider comfort and efficacy for patients and to minimize how scary it can be,” she said.
ECT uses an electrical current to induce a seizure that spreads to deep subcortical structures. MST, which was developed as an alternative to ECT, uses a magnetic field to induce a more focal seizure primarily confined to the cortex.
Although MST has a better side-effect profile, experts noted it has remission rates of 30%-60% compared with ECT. Even one of MST’s inventors, Harold Sackeim, PhD, professor of the Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, is skeptical about its efficacy for TRD.
“I don’t think it works,” Sackeim, who is also the founding editor of Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, told Medscape Medical News.
In addition to being more expensive, MST produces a peak electrical intensity at one-tenth of what a typical ECT stimulus produces. “We’re limited by electrical engineering at this point with MST. That’s my view; others are more optimistic,” he said.
A Lifesaving Treatment
One of the reasons ECT isn’t more popular is because for many patients, it’s easier and more convenient to just take a pill, senior investigator Bradley Voytek, PhD, professor of cognitive science at UCSD, said in the release.
“However, in people for whom medications don’t work, [ECT] can be lifesaving. Understanding how it works will help us discover ways to increase the benefits while minimizing side effects,” he added.
In the first study, which included nine patients with major depressive disorder (MDD), EEG results showed an increase in aperiodic activity following ECT.
The investigators then wanted to test whether these findings could be replicated in a larger study. They retrospectively assessed two previous datasets — 1 of 22 patients with MDD who received ECT and 1 of 23 patients who received MST. After treatment, both groups showed increased aperiodic activity.
“Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST,” the investigators wrote.
The researchers noted that this increase in aperiodic activity is a more parsimonious explanation for observations of clinical slowing than delta band power or delta oscillations for both ECT and MST.”
So why is it important to know exactly how ECT works, and is there any clinical utility to these research findings?
“It’s important for clinicians to give a patient who has questions, a meaningful understanding of what the treatment is going to do, especially with something so scary and stigmatized. The ability to tell a patient why this treatment is working could provide a level of comfort that can assuage some of these fears,” Smith said.
A New Predictor of Response?
In addition, she noted that psychiatry is becoming more focused on predictive indicators for treatment.
“It’s asking: Are there any biological measures that can be used to predict whether someone is going to respond to a treatment or not?” said Smith.
“Aperiodic activity might be a valuable asset to add to that arsenal. Maybe we can better predict which patients might respond to ECT by using this as an additional biological indicator,” she added.
Smith noted that while more studies are needed, it’s exciting that some investigators are already starting to include aperiodic activity as a variable in their research analyses on a variety of topics, such as pharmacological intervention and transcranial magnetic stimulation.
“I don’t know exactly how much utility aperiodic activity is going to have in terms of being a great biological indicator, but I hope that the research will start to play out and reveal a little bit more,” she said.
Sackeim noted that ECT is one of the most misunderstood, controversial, and infrequently used treatments in psychiatry.
“But there’s also no doubt that when you look at ECT, it saves the lives of people with psychiatric illness. Period, full stop,” he said.
He added that although restarting a patient’s heart doesn’t seem to cause unease in the public, the idea of applying electricity to the brain under anesthesia in order to provoke a seizure for therapeutic purpose causes anxiety.
Still, the benefits and harms of a treatment are more important than how it looks, Sackeim said. “If it was only about how it looks, we’d never have surgery,” he added.
‘A Huge Success Story’
ECT was first introduced by Hungarian neuropsychiatrist László Meduna in 1935, and today clinicians “know where the current goes in the brain, at what dosage, and with what path you can get 70%, 80% fully remitted,” said Sackeim.
He noted that in a randomized study published in JAMA Psychiatry, investigators compared the outcomes of MST vs ECT for major depressive episodes in 73 patients. They reported that although depression symptom scores decreased for both treatments, there was “no significant difference” between the two in response or remission rates.
However, in an opinion letter the journal published in April, Sackeim and colleagues Mark S. George, MD, Medical University of South Carolina, and William V. McCall, MD, Augusta University, Augusta, Georgia, strongly questioned the findings.
At less than 30%, “the ECT remission rate after acute treatment was exceptionally low, limiting confidence in the validity and/or generalizability of the findings,” they wrote.
“It’s undoubtedly the case that either if you recruited a sample from whom the treatment may not be as efficacious or if there are issues in delivering them, then you may be finding equivalence” between ECT and MST, Sackeim said.
In addition, he noted that although there have been concerns about cognitive side effects with ECT, they have improved over the years. Sackeim reported that when he entered the field, the average time for a patient to remember their name or the day of the week was 6 hours after receiving unilateral ECT and 8 hours after bilateral ECT. “With modern methods, that’s now down to 10 minutes,” he said.
“The fundamental knowledge is that this treatment can be administered far softer than it ever was in the past. Impressions from the 50s and 60s and portrayed in movies have very little to do with modern practice and with the real effects of the treatment,” Sackeim said.
As for the new studies about aperiodic activity, the investigators are “essentially saying, ‘We have a better marker’ of the process. That way of thinking had in many ways been left behind in the run to study connectivity,” Sackeim said.
He noted that years ago, while he was with Columbia University, his team found that patients who had frontal inhibition were more likely to get well after ECT.
“And that’s essentially the same thing you’re hearing from the UCSD group. They’re saying that the aperiodic measure is hopefully of clearer physiological significance than simply delta [waves] in the EEG,” Sackeim said.
“The idea that inhibition was the key to its efficacy has been around. This is saying it’s a better measure of that, and that may be true. It’s certainly an interesting contribution,” he added.
Sackeim said the takeaway message for clinicians regarding ECT today is that it can be lifesaving but is still often only used as a last resort and reserved for those who have run out of options.
However, he said, ECT is “a huge success story: Maintaining its efficacy, reducing its side effects, getting an understanding as to what the physics of it are. We have some compelling stories about ECT, but even more so, we know what’s not true. And what’s not true are most of the assumptions people have about the treatment,” he concluded.
Smith and Voytek reported no relevant conflicts of interest. Sackeim reported holding patents in ECT technology and consulting with the MECTA Corporation and SigmaStim LLC and other neuromodulation companies.
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