First on CNN: Noninvasive brain treatment for depression proves helpful

(CNN) — Summer passed Valerie Zeko by when she was 27, as she vegged out on the couch watching TV instead of seeing friends or exploring the overcast beach near her house. She later learned that period was her first episode of depression.

“I felt like the fog was in my head as well as outside,” said Zeko, now 57, describing the mood disorder that would squelch her happiness, motivation and self-esteem for 28 years until she finally found effective treatment.

“Everything in my life appeared to be perfect and wonderful, but my head was full of this really bad, negative self-talk constantly,” Zeko told CNN. “I felt like my whole life was falling apart around me. I couldn’t get things done in my house.”

When Zeko first sought help in 2011, her doctor prescribed the antidepressant bupropion, which Zeko took on and off for several years. It made her feel more energized, but sometimes that boost morphed into anxiety. Then Zeko and a psychiatrist tried to tackle her mood disorder with a series of seven other antidepressants.

“They just either didn’t work at all, made it worse, made me feel suicidal,” she said. Other “horrible” side effects included urinary issues, headaches, nightmares, emotional numbness and fatigue, Zeko said.

Zeko’s predicament fit what experts call treatment-resistant depression, which isn’t a formal diagnosis separate from major depressive disorder. Instead, experts may use the term, or TRD for short, to characterize depression unimproved by one or more validated, conventional treatments for depression, said psychiatrist Dr. Brandon Bentzley, cofounder and chief scientific officer of Magnus Medical, a neurotechnology company. Nearly one-third of the 332 million people worldwide with depression fall into the treatment-resistant category.

The year 2023 was when Zeko’s depression “was really bad, when I was desperate,” she said. Though Zeko never contemplated taking her own life, she began to understand why two acquaintances who had died by suicide had considered that an option.

Then a friend recommended that Zeko sign up for a randomized controlled clinical trial testing an innovative, five-day therapy for treatment-resistant depression at Stanford University’s Brain Stimulation Lab in California. Called SAINT, for Stanford Accelerated Intelligent Neuromodulation Therapy, the treatment sends quick magnetic pulses to a targeted region in a patient’s prefrontal cortex. The prefrontal cortex is a core region for emotional and cognitive processing and regulation; its dysfunction is thought to be a key aspect of what causes depression.

Within just the first week or so of receiving SAINT in November 2023, Zeko’s ability to enjoy life — the lack of which is a hallmark symptom of depression — significantly improved.

“Just a few days later, my whole family had Thanksgiving in San Francisco, and we rented e-bikes and rode our bikes across the Golden Gate Bridge,” Zeko said. “I had done this before and never enjoyed it. I was always like, ‘Oh, my butt hurts, it’s freezing, it’s loud, I can’t wait for this to be over.’

“This time, it was a whole different experience,” Zeko added. “I was like, ‘I want to do everything that I have always done again, because it’s so much better now.’”

Zeko wasn’t the only participant who benefited from the trial, the results of which are detailed in a study newly published in the journal World Psychiatry. Half of the 24 participants in the treatment group achieved remission by one month after undergoing SAINT, compared with nearly 21% of the 24 people in the placebo treatment group.

“We have brought mental health treatment into the same precision medicine as the rest of medicine itself,” said Bentzley, a lead developer of SAINT and a lead author of the therapy’s first randomized controlled trial, which was published in 2021. Bentzley’s company, Magnus Medical, holds the SAINT license.

“We do have the tools to … actually understand the human brain on an individual basis, take that knowledge and apply it to treatments in the same way that a cardiologist or cardiothoracic surgeon would on the heart,” Bentzley added.

Typically, the more treatments someone with persistent depression has tried, the less likely the next therapeutic will work for them, which can deepen feelings of hopelessness, said Dr. Ian Kratter, lead author of the new study.

“Potentially showing a treatment can help people even in those circumstances is an incredibly powerful message for patients who are suffering,” added Kratter, clinical assistant professor in the department of psychiatry and behavioral sciences at Stanford University School of Medicine.

The making of SAINT for treatment-resistant depression

Most major mental health treatments — such as some antidepressants or electroconvulsive therapy — were accidentally discovered when initially being used for other diseases, particularly the bacterial infection tuberculosis, Bentzley said. In contrast, formulating SAINT involved “a true engineering process around how the brain worked,” he added.

“We started that process in the early 2010s,” Bentzley said. The team Bentzley is referring to was led by neuroscientist Dr. Nolan Williams, who died by suicide in October at age 43. Williams started Stanford’s Brain Stimulation Lab, the eventual hub for SAINT, in 2015. He had experienced depression himself and never underwent his own therapy, Bentzley said.

“Nolan was an amazing scientist, but he was a healer before being a scientist. That was by far and away more important to him,” Kratter said. “He wanted to get people better faster.”

The team explored which brain area to change to get someone out of depression and back to themselves noninvasively with minimal to no side effects, Bentzley said.

The SAINT technology first obtains a structural and functional MRI of the brain, with the latter providing a window into how different parts are communicating with each other, Bentzley and Kratter explained.

The MRI helps identify the location of the strongest connection between the left dorsolateral prefrontal cortex and a deeper subregion, the subgenual cingulate, which is associated with depression, Kratter said. The researchers then send thousands of rapid signals, or pulses, to that location through the electromagnetic coil inside the stimulator on the participant’s scalp, Bentzley said. These signals cause the connections to become stronger, thus treating depression.

Patients undergo ten 10-minute sessions per day for five consecutive days. The process is faster than conventional transcranial magnetic stimulation, which is also less precise. Conventional TMS can take two to three hour-long treatments weekly for four to six weeks, said Dr. Nina Kraguljac, chair of the American Psychiatric Association’s council on research. Kraguljac, who wasn’t involved in the study, added that the schedule may be difficult for clinics that are understaffed or only running during business hours, but more convenient for patients taking time away from other responsibilities.

While SAINT is administered, some patients feel nothing whereas others feel slight discomfort or pain. “It felt like my whole brain was a rubber band and they were pulling it back and then letting it go, and it would snap back,” Zeko said. “The snaps were very painful but so short that it was not a problem.”

The growing evidence for SAINT

The latest clinical trial adds to several years’ worth of scientific support for SAINT.

In SAINT’s second clinical trial, which had 21 participants but no control group, 90.5% of participants went into remission, Bentzley said. That paved the way for SAINT’s first randomized controlled trial that was also double blinded, meaning neither the participants nor the researchers knew who was receiving which treatment. The placebo treatment replicates every aspect of SAINT except for the magnetic field fully entering the patient’s brain, Bentzley explained. Instead, only a small part enters.

The US Food and Drug Administration cleared SAINT as a therapy for treatment-resistant depression in September 2022 — making it the first rapid, noninvasive neuromodulation system for treatment-resistant depression. The therapeutic is currently available at 17 clinics in the United States.

“We’re looking to hopefully double that by the end of 2026,” Bentzley said.

The new study replicated previous results but in a larger population, Kratter said.

“I think the study is going to be a landmark study in terms of how we think about mechanisms in TMS and how we can personalize treatments using biological markers in the brain,” said Kraguljac, who is also executive vice chair of the department of psychiatry and behavioral health at the Ohio State University.

The study also more objectively measured SAINT’s potential effects on the brain by conducting electroencephalograms, or EEGs, before and after the trial. Those tests involve placing small electrodes on the scalp to record electrical activity in the brain.

The EEGs found SAINT “had a very interesting effect” on beta brain waves, Kratter said —relatively high-frequency brain waves associated with focus, decision-making and concentration. Overactivity in beta waves has been linked to depression and anxiety.

The treatment decreased beta power specifically in “the left anterior cingulate cortex, which is known to be important in emotion and mood regulation,” Kratter said. “The more someone got better, the greater the reduction in the beta range on EEG.”

Additionally, participants with more beta power in that region pre-treatment were more likely to improve, Kratter said. If these findings are replicated, EEG measures may help predict optimal participants and times for the treatment.

“I feel like I’ve walked out of a dense fog,” Zeko said. “Clarity and peace are the main things I feel in my brain now. There’s not a constant negative chatter in my brain anymore.”

Thoughts about sad events stopped causing days-long spirals, and tasks that once felt insurmountable were no longer a second thought. “One of the things I texted was, ‘I came home and unpacked my suitcase immediately, and I didn’t leave it sitting there for like a month,’” said Zeko, referring to messages she sent her friends.

‘What we don’t know is infinite’

Though the latest trial helps explain how SAINT works for some people, “what we don’t know is infinite,” Bentzley said. “The people who don’t get better, their brains look a lot more like what we call ‘healthy controls,’ or people who don’t have depression. And that doesn’t mean that they don’t have depression.”

This means the neurobiology of depression can vary from person to person, even if people have the same symptoms. If that variability truly influences how a patient will fare with different treatments, psychiatry may need to advance how depression is diagnosed and thus treated, Bentzley said.

The EEG findings “still should be viewed as highly preliminary,” said Dr. Paul Holtzheimer, professor of psychiatry at Dartmouth University’s Geisel School of Medicine in New Hampshire. “It could be a mechanism of SAINT or it could be a generic finding when depression improves, regardless of what improves the depression.”

The study population was also largely White, relatively highly educated and had few co-occurring conditions, Holtzheimer said — so how SAINT may work for more diverse groups or ones with more than one diagnosis isn’t fully clear, though this wasn’t the point of the study. Future studies comparing SAINT with conventional TMS and other depression treatments are also needed, though SAINT seems to outperform others in terms of how substantially some patients recover within a short time frame, he added.

“The 50% remission rate is notably higher than what we’ve seen in other studies,” he added.

The researchers also excluded patients who were acutely suicidal or who had attempted suicide in the year prior to the study, noted Dr. Holly Lisanby, founding dean and Foundation Professor of the John Shufeldt School of Medicine and Medical Engineering at Arizona State University. That exclusion for the sake of participant safety is normal in experimental trials, Lisanby, who wasn’t involved in the study, added — but suicidality is also important to consider when comparing SAINT with other treatments in the future.

The durability can vary

What also remains to be seen is more consistent evidence of how long SAINT’s benefits will last. Remission after just one five-day course of treatment has lasted anywhere from several months to years for some participants of various trials. Others have needed a tune-up here and there to remain in remission for a year, Bentzley said.

“For other folks,” he added, “it’s an uphill battle that requires a lot more than just a neurobiological treatment, but also psychological reintegration, occupational treatment and time to relearn the important aspects of how to live a life of genuine remission from depression.”

Relapsing into depression isn’t an issue unique to SAINT; symptoms can still recur with conventional treatments.

The experience of Willow, who has treatment-resistant depression, may represent some of these unknowns. Willow participated in the latest randomized controlled trial in July 2023 but was never told whether she received SAINT or the placebo treatment. This confidentiality is standard for such studies.

Despite that lack of information, Willow thinks she underwent SAINT treatment due to how her mental health shifted during and after the trial.

“On the fourth morning, I walked out of the MRI to head over to the clinic, and a squirrel ran in front of me, and I truly said, ‘Hello, squirrel,’ and smiled,” recalled Willow, who asked that her full name not be used due to privacy concerns.

“I just stopped in my tracks because smiling sometimes feels, with depression, unnatural,” added Willow, who’s 43 and based in California. “The fact that I cared about this little squirrel and thought, ‘Oh, that’s a cute thing’ — I was like, ‘Oh, my goodness, this is definitely something different.’”

Willow’s world felt more vibrant overall, she said, and she began to be more mindful and present with her family and her fellow soccer parents.

The treatment “was beneficial for me for about five months, then unfortunately, I started to notice my depression returning,” Willow said. The trial researchers pulled Willow from the study and gave her another round of SAINT in February 2024, which relieved her symptoms for about six months. Since October 2024, she has managed her depression with weekly ketamine treatments administered by a doctor.

Now over two years since Zeko received SAINT, she has started feeling depressed again in the past six months, she said. But her symptoms may just be from losing her dream job and now working in a nonideal job rather than signs of a relapse, she said. She has been trying to get her insurer to cover a potential next round of SAINT but said the company denied her claim, saying she hasn’t sufficiently explored all her options. Stanford is helping her try to contest the insurer’s decision, she said.

What SAINT could mean for psychiatry

Kratter and Bentzley are hopeful for what the SAINT trials could mean for the broader population with treatment-resistant depression, but other hurdles remain — including awareness and insurance coverage.

Of the people in the US who need transcranial magnetic stimulation, only 0.7% get it, Bentzley said. “That technology has been out for nearly two decades with FDA clearance and has a mountain of evidence.”

The SAINT therapy generally isn’t covered by most private insurance plans, but some companies are considering it or offering coverage in some states. Medicare covers SAINT in hospital-based, outpatient settings. Without insurance, one course of SAINT can cost roughly from $16,000 to over $30,000, Bentzley said. The therapy is only available through clinics supported by Magnus Medical or a clinical trial supported by Magnus Medical or Stanford, he added. “There are numerous clinics that advertise they provide SAINT but actually do not.”

“The hope is that brain stimulation technologies … can be moved up earlier in the so-called treatment algorithm,” said Kratter, referring to treating people with treatment-resistant depression and those who would rather do a potentially one-off treatment like SAINT instead of trying pharmaceuticals and experiencing negative side effects. But whether SAINT could also be a first-line treatment for general depression hasn’t yet been studied.

“We all dream about a major cultural shift in how we treat this population, and the optimistic side of me wants to see that happen fast,” Bentzley said. “But historically, those types of changes take several decades.”

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