ECT, MST, and Other Neuromodulation Therapies to Relieve Severe Psychiatric Illness
Dr. Lisanby has been deeply involved in developing new technologies to stimulate the brain such as MST (magnetic seizure therapy) and improving existing treatments like ECT (electroconvulsive therapy), which can save lives of people with severe psychiatric illness. Reducing or eliminating the impact of seizure-based therapies on memory is a particular objective, with success that has been demonstrated in clinical trials.
Sarah Hollingsworth “Holly” Lisanby, M.D.
Director, Noninvasive Neuromodulation,
Unit, Experimental Therapeutics & Pathophysiology Branch,
Intramural Research Program,
The National Institute of Mental Health (NIMH)
Director, Division of Translational Research, NIMH
BBRF Scientific Council
2010 BBRF Distinguished Investigator
2003 Independent Investigator
2001 BBRF Klerman Prize for Exceptional Clinical Research
1996 Young Investigator
While she was a medical student at Duke University Medical Center—after earning undergraduate degrees in mathematics and psychology at Duke—Dr. Sarah Lisanby had an experience that would deeply influence the course of her career.
“I had a patient with catatonia, a very serious, even life-threatening condition in which the person can’t speak, can’t eat, can’t move.” Catatonia is sometimes seen in patients with mood disorders, including major depression, as well as in schizophrenia and other disorders featuring psychosis. In this case, catatonia occurred in the context of a major depressive episode, and the treatment prescribed was electroconvulsive therapy (ECT).
ECT, which is well known to be highly effective (up to 80%) and rapid-acting (2–4 weeks), is designed to induce a brief therapeutic seizure in the brain of the patient, who receives the treatment while under general anesthesia. It is underutilized relative to other treatments, even ones likely to be less effective. This is because of ECT’s impact on memory; some degree of impairment frequently follows treatments for some period of time, before, typically, resolving or lessening.
In this seriously ill patient, the potential benefits of treatment were deemed to outweigh side-effect risks relating not only to memory loss but also to any treatment that involves placing someone under general anesthesia.
A typical course of ECT therapy is 6 to 12 sessions (3 per week) over 2 to 4 weeks. Dr. Lisanby attended the catatonic patient’s first ECT session. “On the afternoon of her first treatment,” she recalls, “she started speaking. This was a really amazing experience—to see someone go from death’s door to having a dramatic improvement after a single treatment. It really piqued my interest in ECT. How does it work? My mentor at the time, very well known in the field of ECT therapy, replied, honestly: ‘Well, we don’t exactly know.’”
“I thought: wow; this is a powerfully effective treatment with a lot of mystery and misunderstanding surrounding it. That attracted me. Primarily because I saw how beneficial it was and thought maybe I could learn more about how it works.” Learning how it works was a potential starting point for thinking about how to reduce the side effects of ECT, and also, as Dr. Lisanby would discover, a basis for exploring a range of other technologies also involving the modification of electrical activity in the brain—neuromodulation—to generate therapeutic results for patients with incapacitating psychiatric illnesses.
‘THE BODY ELECTRIC’
Many of us have an almost automatic fear of electricity when it is mentioned in connection with the body. We all learn as children to avoid dangers associated with live wires and the shocks they can deliver. The use of electricity in ECT for treatment of psychiatric conditions—first attempted in 1938 with technology that today would be regarded as primitive—has been explicitly presented to the mass audience over the years as a frightening procedure, perhaps most damningly in the 1975 film One Flew Over the Cuckoo’s Nest. One inaccuracy in that film is the depiction of a patient having convulsions while the therapy is being administered. This never happens in the modern application of ECT, in which the patient is premedicated with strong muscle relaxants that prevent convulsions. The procedure, conducted while the patient sleeps, is brief and painless.
Lingering fears about electricity-based treatments of brain disorders can be confronted with several basic facts. The most important is that the brain is an electrochemical organ. Neurotransmitters like dopamine and serotonin act at the trillions of synapses, or points of connection, between neurons. But it is electrical energy within nerve cells that makes them fire: after chemicals bind at neuronal receptors, an electrical signal is triggered whose intensity, if above a certain threshold, will induce an “action potential” that sends an electrical pulse down axons and dendrites to other neurons. In other words, as Dr. Lisanby puts it, “neurons speak to each other using both chemical and electrical signals.”
Another basic fact: not only are electrical fields generated by components of the brain; the brain also responds if you apply electrical fields to it, whether from the outside or within the brain itself. Precisely what happens within the brain when ECT is applied is part of what research on ECT has sought to discover as its safety profile has been steadily improved.
Before tackling this subject, Dr. Lisanby makes a point about stigma. She stresses that “the stigma surrounding ECT isn’t just unfortunate. It is deadly. Stigma can prevent people from getting life-saving treatments.” Or as she put it on another occasion: “Depression kills, while ECT saves lives.” This should hit home with particular force, she says, in the context of current trends in suicide. Just shy of 50,000 Americans ended their lives by suicide in 2022 according to statistics just released by the National Center for Health Statistics. There is no question that ECT is among the most effective treatments in addressing suicidal crisis in inpatient settings. “So I think it’s really important to de-stigmatize, to call this out” she says.
“We need to think about ‘the body electric’: our brains are electric. But so are our hearts and muscles. Without electricity in our bodies, we wouldn’t be able to walk and our hearts would not beat. And we wouldn’t be able to think. When you get an EKG, you are seeing an electrical rendering of how your heart works; and when the heart gets an arrythmia, the normal rhythm can be restored using electricity in the form of a pacemaker. When a life-threatening ventricular fibrillation occurs, you give a defibrillation with paddles to normalize the rhythm—and that’s using electricity, applied to the chest.”
‘IS IT THE ELECTRICITY—OR THE SEIZURE?’
Few people think twice about these applications of electrical energy to save lives in other medical contexts. As a psychiatric resident at Duke, Dr. Lisanby did not think twice about using ECT in the context of serious brain- based illnesses after she witnessed that it too can save lives. After her residency, she earned a fellowship at the New York State Psychiatric Institute (NYSPI), affiliated with the Department of Psychiatry at Columbia University. The year was 1995, the same year she and others read the first published study about a then-new technology called TMS (transcranial magnetic stimulation). Unlike ECT, in which electricity is delivered into the brain via electrodes placed on the scalp, TMS involves placing a magnetic coil above the scalp to generate magnetic fields that penetrate the brain and induce an electrical current to which the neurons in the brain respond. It is a way of using magnetism from outside the brain to alter electrical activity within it.
TMS was specifically designed to modify electrical activity in the areas just beneath the scalp—outer layers of the prefrontal cortex that lay just beneath—but not to cause a seizure. In ECT, when the brain experiences a brief seizure, it is because the electricity delivered is above the excitation threshold of most neuronal tissue. This results in activation of essentially the entire brain, and this universal activation causes the brain to seize for some seconds. (Seizures induced in this way end, it is thought, because of the action of inhibitory neurotransmitters, which are released across the brain during the seizure.)
“The dogma of the day,” says Dr. Lisanby, thinking back to the mid- 1990s, “was that you’ve got to induce a seizure” to get a therapeutic effect—whether in treatment-resistant depression or refractory psychosis or catatonia. “I approached this question as a scientist and a pragmatist.” It was the ostensible aim of her fellowship project to bring TMS to Columbia and to learn about how it works. “But the idea was also to understand seizures better. There was a lot of skepticism about whether TMS could work or not because it did not induce a seizure.”
Ultimately, the big question about electrically altering brain activity to generate a therapeutic effect continues to be, in Dr. Lisanby’s words, “is it the electricity or is it the seizure, or is it both?” The question is still under study, although it has long been clear that TMS and other therapies that do not induce seizures can have important therapeutic effects. The question now is whether the efficacy of ECT depends upon the induced seizure.
While learning about TMS at Columbia and using TMS, in effect, to study ECT, Dr. Lisanby developed a novel technology that was neither ECT nor TMS—a neuromodulation technology that her name is today perhaps most closely associated with: magnetic seizure therapy, or MST. It utilizes more powerful magnetic fields than are used in TMS to induce electrical activity in the brain that are just sufficient to cause a brief seizure. “We wondered: could we induce a seizure with very little electricity? It might be a way to try to understand what the seizure itself is doing without the overlay of the stronger electric field that’s used with ECT.” There was also the possibility that a seizure induced with MST might help improve the safety of ECT, perhaps in part by minimizing or eliminating memory loss.
In the early 2000s, Dr. Lisanby’s collaborations with MST pioneers in Wales, UK and Bern, Switzerland led to the first tests of MST in humans. “The first [depressed] person we treated, in Bern, got better, and that gave us the signal that we might be on to something,” she remembers. A first clinical test in the U.S., led by Dr. Lisanby at Columbia/NSYPI, provided a first indication that MST might indeed be safer than ECT in terms of its cognitive side effects. But at that time, it was not yet clear if MST was as effective as ECT in reducing symptoms of major depression. Both the side effects and efficacy of the two methods have been the subject of research ever since, as improvements have been made in both approaches.
In 2005 Dr. Lisanby’s innovation and leadership in neuromodulation was recognized by Columbia, where she became founding director of the Division of Brain Stimulation.
In 2010 she was recruited back to Duke University where, in the department of Psychiatry and Behavioral Sciences, which she chaired, she founded the Duke Division of Brain Stimulation. Five years after that she was recruited by the director of the National Institute of Mental Health, Dr. Thomas Insel, to lead research on neuromodulation therapies in the intramural research program at the Institute, as well as the Division of Translational Research on the extramural side of NIMH. She was founding director of the Noninvasive Neuromodulation Unit in the NIMH Intramural Research Program and co-led the NIH BRAIN Initiative Team focused on development of large- scale neural recording and modulation devices.
BRAIN STIMULATION VS. DRUG TREATMENTS
Today, more than two decades after Dr. Lisanby began learning about, testing, improving, and developing new neuromodulatory approaches, a great deal is known about them that was not known then. TMS is the technology that has gained the widest acceptance and now is used to treat many thousands of people annually with depression and OCD, and to a lesser extent, other neuropsychiatric conditions. TMS has evolved over these years, as has been reported in this magazine, but so have ECT and MST, the two methods that were the initial focus of Dr. Lisanby’s research.
All forms of neuromodulation used today are in basic ways unlike currently used drug therapies to treat psychiatric illnesses. Some of those differences are potential advantages. Dr. Lisanby and two co-authors, William T. Regenold, M.D. (a 2010 BBRF Independent Investigator and 2000 Young Investigator) and Zhi-De Deng, Ph.D. (a 2017 BBRF Young Investigator), talk about this in a “Review Article” published in 2021.
“As a family of interventions,” they note, “neuromodulation devices are distinct from pharmacological therapies in several respects.” Therapeutic medicines target receptors in cells, where they bind, causing a cascade of “downstream” effects which impact a range of biological functions. In contrast, devices that use magnetism or electricity to modulate the brain target the electrical properties of neurons and the axons and dendrites that connect them. Medications, when ingested, are distributed throughout the body (and brain, when they can penetrate the blood-brain barrier), while neuromodulation devices directly apply electric fields to brain structures—sometimes with great specificity (it depends in part on the device). Also, unlike medicines, which reach a “steady-state” level in the blood and then decay over varying periods of time, neuromodulatory devices can apply stimulation to neurons, brain circuits, and brain regions at specific times relative to ongoing neural activity—which can be monitored in real time, via functional brain imaging.
In sum: there are ways in which brain stimulation can do things that drugs cannot. The spatial specificity of brain stimulation is especially important in understanding how modern ECT has improved over previous iterations of the technology. Making ECT safer with respect to cognitive side effects has been the product of experimentation involving different ways of placing the electrodes on the scalp that deliver electrical energy to the brain.
By moving from the old standard “BT” configuration (bitemporal ECT) to “RUL” (right unilateral) and “BF” (bifrontal) configurations, electrodes have been repositioned [see illustration, facing page] with the aim of reducing cognitive side effects, while maintaining the largest amount of therapeutic efficacy. By directing electric fields generated by the electrodes away from the dominant temporal lobe of the brain, memory loss associated with the treatment has been significantly reduced. “We’re sculpting where the electric field is going in the space of the brain,” Dr. Lisanby says.
This improvement in the spatial dimension of the treatment has been accompanied by improvements that pertain to the temporal dimension. By literally changing the shape of the electrical waves being delivered by the electrodes, it has been possible to substantially improve safety. “Shortening the duration of the electrical pulses also dramatically reduced cognitive side effects,” Dr. Lisanby explains. “Brief pulse” ECT was developed, and then “ultrabrief pulse,” which, when used in combination with right unilateral placement of electrodes (RUL), offers the safest form of ECT yet used in the clinic. The changes were of sufficient magnitude to lead the FDA to reclassify ECT in 2018 as a “moderate risk” class II medical device (it had formerly been rated “higher risk.”) The new classification applies to the use of ECT specifically in individuals age 13 and above with catatonia or a severe major depressive episode associated with major depressive disorder or bipolar disorder. ECT is also used to treat manic and mixed episodes of bipolar disorder, schizoaffective disorder, treatment-resistant schizophrenia, and a kind of treatment-resistant epilepsy that features long-lasting seizures (status epilepticus).
There is still considerable mystery surrounding exactly how ECT delivers major reductions in a variety of psychiatric symptoms. When all of the cells of the brain are firing together, inducing a seizure, says Dr. Lisanby, “it powerfully releases all of the neurotransmitters that the brain runs on, and it induces neuroplastic changes [changes in the strength of connections between neurons] that last beyond the seizure itself and that convey powerful antidepressant effects and antipsychotic effects, among other changes that are helpful clinically in a number of severe disorders.” In major depression, ECT needs to be given periodically, with the benefits from treatment often lasting half a year, or more in some cases. Longer lasting remission can be achieved by using a relapse prevention strategy, such as continuation ECT and combination pharmacotherapy.
PROGRESS WITH MST
“If it is the seizure that is driving the therapeutic benefit of ECT, and if it is the electricity that is driving the side effects, then inducing a seizure with a minimum of electricity could be a way of maintaining the antidepressant effects of ECT without the cognitive side-effect burden,” Dr. Lisanby reasons.
“Our studies and those of others suggest MST can have comparable antidepressant effects as ECT—and that MST carries less cognitive side effects. That’s our goal: we want to have the benefit of the seizures without the downside of the memory loss.”
In an important paper appearing in JAMA Psychiatry in December 2023, Dr. Lisanby and colleagues compared MST and ECT in 73 “severely ill” patients with refractory depression in a double- blinded, randomized clinical trial conducted at three academic hospital locations. A typical participant, about 48 years old, was in the third year of a current major depressive episode; 10 were suffering from bipolar depression. Thirty-five participants were treated with MST and 38 with what is considered the safest version of ECT yet employed (ultrabrief pulse right unilateral [RUL] ECT). Patients received three treatments per week until they either reached remission (60% or greater reduction in symptoms) or a “plateau” response.
The trial provided evidence “for substantial advantages” of MST relative to a version of ECT. “Both MST and ECT demonstrated clinically meaningful antidepressant effects. There was no significant difference between ECT and MST for either response or remission rates,” the team reported. “Both MST and ECT showed a sustained benefit over a 6-month follow-up period, again with no significant difference between them.”
MST and ECT results differed in two respects. One was that it took, on average, 2 or 3 more MST sessions for patients to achieve remission compared with ECT. The other had to do with what researchers call “time to orientation.” This is the amount of time it takes patients to reacclimate after awakening from anesthesia. A longer time to orientation is a predictor of the severity of post- treatment amnesia—the memory loss that is associated with ECT, but, so far, not MST. In this trial, MST patients reoriented in a few minutes, compared with about a 20-minute period, on average, for ECT patients. This result is “consistent with previous reports on MST that found that cognitive adverse effects are negligible.” In fact, MST patients “exhibited superior performance on both autobiographical memory recall and specificity,” the team noted. MST patients “also reported significantly fewer subjective adverse effects,” including fewer physical adverse effects such as headache, nausea, and muscle pain, in addition to less post-treatment confusion or disorientation.”
What do these results mean to Dr. Lisanby? “I think they justify further work. What we aim for is real-world impact. To have treatments that are clinically available that are really helpful to people who are suffering with severe conditions means that MST will need FDA approval. The next step is a noninferiority trial, a larger trial that is adequately powered to test whether MST is truly non-inferior to ECT. If the FDA were to find MST safe and effective it could potentially be cleared for clinical use in the future.” The NIMH is supporting such a trial, which is called the Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) study, and it is now enrolling patients.
“We look at the national suicide rates. We need to do something about that. We already know that ECT is powerfully effective and rapidly acting at preventing suicide, and yet it is underutilized. And so anything we can do to get the benefits of ECT without the barriers, like the risk of memory loss, into the hands of people who need it—this is our goal.”
MORE RESEARCH, MORE OPTIONS
Recent variations of rTMS therapy such as SAINT, the protocol involving a 5-day course of accelerated brain stimulation therapy, developed at Stanford University by two-time BBRF Young Investigator and Klerman Prize winner Nolan R. Williams, M.D., and colleagues, is rapid acting and shows considerable promise for addressing patients in suicidal crisis. So does inpatient administration of the experimental drug ketamine or its FDA-approved derivative, esketamine. Yet while these drugs have benefits that can be dramatic, it is not yet known how long-lasting they are, especially when compared with the duration of ECT and MST benefits as demonstrated in the newly published study.
Dr. Lisanby directs an NIMH division that is charged with furthering therapies of many kinds, including neuromodulatory interventions. As director of her lab and division, it is her goal “to provide clinicians with more options.” That means the NIMH is sponsoring clinical trials not only to test MST but a wide range of other potential neuromodulatory therapy approaches. One trial under way in her lab, called iLAST (individualized low-amplitude seizure therapy) seeks to generate MST-like effectiveness using an ECT device that employs less electricity and five small closely spaced electrodes rather than two in most ECT and MST applications. The idea here is to more narrowly and precisely focus the electric field in the brain, with the aim of further reducing cognitive and other side effects.
Another NIMH-backed trial in her lab called TEST (transcranial electric stimulation therapy) involves delivering brain stimulation with an ECT device operating below the seizure threshold. It’s applied exactly as standard ECT, and under anesthesia, but in doing so without causing a seizure, it is hoped that TEST may generate efficacy with a minimum of cognitive side effects.
Efforts are also under way to achieve greater personalization of TMS and related brain stimulation approaches. This involves improving targeting and experimenting with ways to reach areas deep in the brain that were once thought inaccessible to the superficial penetration of electromagnetic waves generated by TMS and related technologies. An example of this is using neuroimaging to target the brain’s subgenual cingulate cortex (sgACC) “transsynaptically,” via TMS, in a study that was also supported by BBRF.
Finally, says Dr Lisanby, there are a number of completely new technologies whose development is supported by the NIH’s Brain Initiative. Two such technologies involve the use of light and sound waves, as opposed to electricity or magnetism, to alter the function of brain circuits implicated in psychiatric illnesses. “We are on the frontier of figuring out how to harness different forms of energy to influence brain function and study and promote brain health,” says Dr. Lisanby. “It’s a pretty exciting time.”
Written By Peter Tarr, Ph.D.