New wave psychiatry

During the past century, psychiatry has been stuck in a rut. In the beginning, there was talk therapy to help patients recognize internal conflicts that generated negative thoughts and behaviors. Then there was psychopharmacology, the use of mood-altering drugs. While these approaches worked for some, they left many patients without hope.

Enter a new wave of psychiatric treatments based on an ancient approach to healing the brain — electricity.

Back in A.D. 46, Roman physician Scribonius Largus treated migraines by placing a live electric torpedo fish “on the place which is in pain, until the pain ceases and the part grows numb.” Over the millennia, there have been variations on this theme — shock therapy and deep brain stimulation, to name a few. But none of these treatments have been practical or safe enough to use in mainstream psychiatry — especially the torpedo fish.

Now, a Stanford Medicine research team is developing a noninvasive, more targeted electromagnetic treatment that can improve mental disorders like depression in a week or less with long-lasting relief. Called Stanford neuromodulation therapy, or SNT, it uses a magnetic paddle placed on the scalp to deliver gentle electrical pulses that reset brain circuits that have gone awry.

This next generation in transcranial magnetic stimulation is successfully treating severe depression in people for whom other approaches have failed. In a small double-blind, randomized clinical trial, nearly 80% of the 14 participants went into remission after five days. Follow-up studies have shown similar results, with about half of the participants remaining depression-free four weeks after treatment.

The Stanford University Brain Stimulation Lab has led the charge to refine this technology, incorporating new knowledge about functional brain circuits and learning theory to recalibrate misbehaving brain networks for conditions that include bipolar disorder, addiction, borderline personality disorder and obsessive-compulsive disorder.

Brain training

The Brain Stimulation lab director, Nolan Williams, MD, didn’t have a roadmap for a career in psychiatry and neurology growing up in Charleston, South Carolina. Both parents were blue-collar workers without college degrees. Though he met some medical professionals while attending the Academic Magnet High School in North Charleston, he attributes most of his success in medicine to early training in martial arts.

“I started taekwondo when I was 8 and was granted a black belt at 15. I won two world championships in college,” said Williams, 41, whose laid-back demeanor and shoulder-length auburn hair project more of a surfer vibe than that of a psychiatrist. (He also kitesurfs.)

Taekwondo taught him that success in life boils down to five principles: courtesy, integrity, perseverance, self-control and indomitable spirit. He believes in the repetitive mind-body drills that both taekwondo and medicine require to build skills and perform at a high level.

“When you step into the ring, you know there’s going to be a fight,” he said. “You have to be fully present in that moment, not thinking about the future or the past.”

Today, Williams is an associate professor of psychiatry and behavioral sciences focused on building better tools for treating mental illness. His research spans a wide range of solutions, from rapid-acting psychedelics to retraining misfiring brain circuits.

“I’m an agnostic psychiatric tool builder. If it’s safe for the patient and the risk-benefit ratio is right, we’ll look at it. My job is to find tools that can help people feel more like themselves.”

Nolan Williams, MD, associate professor of psychiatry and behavioral sciences and director of the Brain Stimulation lab

Williams entered the nascent field of electrical brain stimulation in 2006 as a medical student under the mentorship of Mark George, MD, a professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. George pioneered the use of transcranial magnetic stimulation, TMS, for mapping mood-regulating brain circuits and was the first to identify the cingulate cortex as a brain region that plays a role in depression. He conducted some of the first clinical trials of TMS for treating persistent depression, and his six-week protocol was approved by the U.S. Food and Drug Administration in 2008.

After completing dual residencies in psychiatry and neurology and a research fellowship with George, Williams came to Stanford Medicine as an instructor. It seemed like an excellent place to take TMS to the next level. The chair of the Department of Psychiatry and Behavioral Sciences, Laura Roberts, MD, was supportive of the new frontier of interventional psychiatry and breaking down walls between neurology and psychiatry.

Stanford Medicine’s academic ecosystem fostered collaborations between medicine and engineering, leading to discoveries in brain-circuit mapping, genetics and the use of light to influence brain activity. Another advantage: The campus is located at the epicenter of a thriving biotech community and venture capitalists willing to invest in paradigm-busting ideas. So, Williams stepped into the ring and began building a team to tackle depression — one of the most disabling and costly medical conditions worldwide.

Dream machine

Sergio “Checo” Gonzales left his home in rural Northern New Mexico in 2010 to pursue undergraduate and medical degrees at the University of New Mexico. His driving passion is to improve the health care disparities that he witnessed as a child. His research is focused on mathematical modeling of complex social systems in resource-poor communities.

He loves academic research, and he’s had visiting scholar stints at Harvard, Wharton and Washington University School of Medicine. He even learned Diné Bizaad, the Navajo language, so he could form deeper connections with members of the Navajo Nation for whom he was providing health care. In this culture, he would be called an azee’ííł’íní, one who makes Western medicine.

Today, this work is on hold, as he struggles with depression, specifically anhedonia, a lack of interest, enjoyment or pleasure from life’s experiences.

“The most challenging aspect of it is my inability to feel any kind of emotion,” Gonzales said. “I can intellectualize the importance of my research, my fiancée, my dogs and my family, but I am often paralyzed with the idea that I’m a worthless person who doesn’t want to be on this earth.”

“I was contemplating taking my own life and really struggling to complete daily tasks needed to make progress in my academic career.”

Sergio “Checo” Gonzales, a particiant in and SNT trial whose depression led him to take a leave of absence from medical school at University of New Mexico

While he thinks he may have suffered from undiagnosed depression since childhood, severe symptoms emerged during the first year of medical school, when he realized that he needed to find an environment more supportive of all his talents and academic interests. He also faced significant barriers to finding psychotherapy and pharmacotherapy that worked for him.

“I was contemplating taking my own life and really struggling to complete daily tasks needed to make progress in my academic career.”

To survive, he took a leave of absence from medical school and began work toward a PhD in biomedical data science at Stanford Medicine. After a couple of rough years during the COVID-19 shutdown, his psychiatrist enrolled him in the SNT clinical trial, which was transformative.

“It was like magic,” Gonzales said. “Over two days, I went from feeling like death was the only way to end my suffering to my normal self, excited to live the rest of my life. The only side effect was that I felt great.”

The remission enabled him to return to his studies and pick up the pieces of his life. Nearly all his symptoms disappeared. But over the following three months, symptoms crept back. Now he’s in a holding pattern, back in intensive psychotherapy and finding no relief with multiple trials of pharmacotherapy, waiting until he can resume the “magic” SNT treatments when they become available to the public.

The discovery process

One in 5 people suffer from depression in the United States, 322 million worldwide. The economic burden of major depressive disorder among U.S. adults is immense, estimated at $326 billion in 2018 (in 2020 dollars).

But some of the most devastating impacts of depression are immeasurable — broken families, abandoned jobs, hospitalizations and suicides. More than 700,000 adults in the U.S. die by suicide annually, and it is the fourth-leading cause of death among 15- to 29-year-olds.

Before SNT, there were no quick fixes for people who sink into life-threatening despair. Talk therapy takes months to years to be effective. Antidepressant drugs must be taken for four to six weeks before benefits are felt — if those medications work. TMS requires at least six weeks of treatments. But SNT, a type of accelerated TMS, can improve depressive symptoms in less than a week.

Breakthroughs with SNT were twofold. The first was the discovery that electricity flows backward in the sadness-control brain circuit of many people with depression. The second was that dysregulated circuits could be retrained more quickly by administering a more intense pattern of magnetic pulses over a shorter period.

Anish Mitra, MD, PhD, now an assistant professor of psychiatry and behavioral sciences, was instrumental in the lab’s discovery of the backward circuit problem. As a graduate student at Washington University in Saint Louis, Missouri, he developed a mathematical tool to identify active areas of the brain through analysis of brain scans. His tool could measure tiny timing differences in the blood flow to various brain circuits, which, in turn, revealed the direction of electrical flow through these circuits.

“What’s liberating is that it showed me that depression doesn’t have to be my identity — it’s just a function of my brain biochemistry that can be fixed.”

SNT trial participant Sergio “Checo” Gonzales

When they used this tool to analyze severely depressed patients, they noticed that electricity flowed through the emotional control brain circuit, the left dorsolateral prefrontal cortex, in the wrong direction from healthy controls. Moreover, if they sent electrical pulses against this current, they could fix it, much as a pacemaker resynchronizes an irregularly beating heart.

Williams thought about this new finding in the context of his martial arts training and new research on optimal learning. He knew that the six-week, low-intensity TMS treatments weren’t fast enough for patients in crisis situations. His hypothesis was that more repetitive, high-intensity bursts would be more effective, using the same learning strategies that people use to study for exams or prepare for a taekwondo competition.

After some trial-and-error studies, he found an optimal pulse pattern for treating major depressive disorder. Next, his team designed a clinical study to assess the efficacy of this approach, and he became the first to treat real-world patients with SNT, targeting the depression brain network of neurons originally discovered by Michael Fox, MD, PhD, at Harvard Medical School.

In 2021, the FDA designated SNT as a “breakthrough therapy,” which put it on a fast track through the regulatory approval process, because of its potential to treat a serious condition much more effectively than existing therapies. Then in 2022, the FDA cleared the SAINT neuromodulation system as a Class II medical device, which combines SNT stimulator hardware and software with a neuronavigation tool for identifying a personalized brain target. It is the first noninvasive, rapid-acting neuromodulation approach to treatment-resistant depression.

Treatments are delivered in 10 50-minute sessions per day, over five consecutive days. It’s painless and noninvasive. Patients can watch movies or read during the sessions. The most common side effect is a headache that dissipates in a few hours.

How it works

SNT magnetically induces electrical flow through the “wiring” of a brain, the neurons, with gamma frequency bursts overlayed on theta waves. Theta waves are natural brainwave oscillations of 4 to 8 hertz (cycles per second) that are believed to be involved in the creative flow state and implicit learning. Gamma brain waves are the fastest brain waves, oscillating at a frequency of 30 to 90 hertz, and have been found to foster receptivity, happiness and the ability to concentrate.

The treatment begins with a resting-state functional magnetic resonance imaging (fMRI) brain scan that determines the exact location of an individual’s emotion-controller center. Next, a wand containing wire-wrapped magnetic rings, called toroids, is precisely positioned on the scalp just above the left side of the forehead. The coils deliver a shallow field of waves that harmlessly travel through the skull and induce a gentle flow of electricity through the brain’s emotional-control network. The objective is to strengthen the dorsolateral cortex’s role in suppressing the sadness region of the brain.

During the first double-blind, randomized clinical trial of SNT, 29 people with treatment-resistant depression were enrolled. Half received the new treatment, and the rest were given a sham treatment to rule out placebo effects. After five days, 78.6% of the treated group were no longer depressed, and some felt their depression lift after only a few days.

Within two weeks, thoughts of suicide improved dramatically in this group. Remission rates in this trial and follow-up studies have yielded similar results, with 46% to 57% of treated participants reporting sustained depression relief four weeks after treatment. Some patients report being in remission for a year.

The study also showed that SNT doesn’t work for everyone with depression, only for those with a malfunctioning sadness-control brain circuit — and researchers discovered that the more severe the depression, the more signals were traveling the wrong way. This observation has opened a tantalizing possibility: Maybe they could use fMRI brain scan flow patterns to help diagnose mental conditions, adding another tool to the psychiatric toolbox.

Fighting the system

Designing innovative new medical hardware is hard. Getting it through the regulatory gauntlet and into clinics is even harder.

Williams’ ally in this effort is Brandon Bentzley, MD, PhD, a psychiatrist, technologist and neuroscientist who first met Williams at the Medical University of South Carolina.

“We were both molded in the incredible neuroscience community at MUSC, a community that framed brain function in terms of circuits,” Bentzley said. “In meeting Nolan, I was struck by our parallel ambitions to create new treatments for mental health based on a mechanistic understanding of the human brain.”

A year after he graduated, Bentzley followed Williams to Stanford Medicine for his psychiatry residency, and they began talking about the potential of TMS and how to get this promising new technology into the medical system.

In the past, treatments for mental illness were almost always the result of accidental findings. Antidepressants were discovered by observing the mood-altering effects of drugs being tested to treat tuberculosis. Antipsychotics were discovered while testing new types of anesthesia. Bentzley and Williams, on the other hand, set out from the beginning to design a treatment for depression rooted in an understanding of the underlying neurocircuitry of the brain.

“In meeting Nolan, I was struck by our parallel ambitions to create new treatments for mental health based on a mechanistic understanding of the human brain.”

Brandon Bentzley, MD, PhD, a psychiatrist, technologist and neuroscientist

“Based on the efficacy and speed of the SNT treatment protocol, my hope is that we can use this technology as a generalizable platform where brain mapping is married to neuromodulation to provide effective treatments for many brain illnesses,” Bentzley said.

In 2020, Bentzley co-founded Magnus Medical Inc. to commercialize a system for SNT treatment — the SAINT neuromodulation system — while Williams continues his research on refining neuromodulation and applying it to other disorders. (Williams has equity and stock options in Magnus Medical.)

“Implementing technologies like this requires a shift in health care,” Bentzley said. “Reimbursements for mental health hospitalization haven’t changed in 20 years, and there is no easy way for these institutions to adopt new interventions.”

Mainstreaming SNT requires mental health care providers to have access to fMRI services, to purchase expensive new equipment and to train staff to operate it. To justify these expenditures, the company will have to educate the psychiatric community of its effectiveness and gather enough cost/benefit data to convince the federal Centers for Medicare & Medicaid Services (CMS) and more than 1,000 medical health insurers to reimburse institutions for prescribing these treatments.

Earlier this year, SAINT secured CMS reimbursement approval for treating major depressive disorder under “new technology add-on payments.” Historically, once a treatment receives CMS approval, other medical insurance plans add it to their list of reimbursable procedures.

Bentzley’s strategy is to launch in large institutions for the most urgent cases of major depressive disorder, then move their systems into smaller clinics. Ongoing work will focus on making the integrated software-hardware system easier for staff to learn and use. The company will add protocols for other mental conditions as soon as they receive FDA approval.

What’s next

Williams’ Brain Stimulation Lab has about 15 faculty and postdocs working on fast-acting therapies for psychiatric disorders. Targets include treatment-resistant depression, obsessive-compulsive disorder, mania, addiction, chronic pain, borderline personality disorder, depression associated with Parkinson’s disease and persistent tic disorders. Recently, the researchers in the lab identified a brain circuit that makes people more susceptible to hypnosis, which could be leveraged to make it easier for patients to overcome addictions such as smoking.

Williams’ peers and collaborators said they believe that SNT is the start of something big, though there’s still a lot of work to be done before it is fully implemented into clinical care at scale.

Claudia Padula, PhD, an assistant professor of psychiatry and behavioral sciences and addiction researcher at the Sierra Pacific Mental Illness Research, Education and Clinical Center at the VA Palo Alto Health Care System, thinks TMS and SNT are still in their infancy for treating alcohol abuse disorder: “We have a lot to figure out, in terms of mechanisms of action, optimal sites, and the number of sessions and pulses … but the trajectory is looking really promising.”

Corey Keller, MD, PhD, an assistant professor of psychiatry and behavioral sciences, has been using TMS for years. As a researcher who runs a lab focused on personalized brain stimulation treatments, he is excited about having an FDA-cleared protocol as a launching point for next-generation technologies.

“For the past 15 years, TMS treatments have been largely nonpersonalized and one-size-fits-all,” Keller said. “TMS can apply millions of different patterns of stimulus. We can personalize the treatment target and intensity of stimulation, as is done in SNT. We are also close to being able to update stimulation patterns in real time, or after every treatment, to measure how much of the brain we’re changing and have that guide treatment. SNT represents an exciting next step in moving in this direction of personalized TMS.”

“We are … close to being able to update stimulation patterns in real time, or after every treatment, to measure how much of the brain we’re changing and have that guide treatment.”

Corey Keller, MD, PhD, an assistant professor of psychiatry and behavioral sciences

While Keller is enthusiastic about SNT, he also sees some challenges. It is unclear how this new treatment protocol will be adopted in clinics. The fMRI and neuronavigation equipment required to precisely position the magnetic coils may limit uptake in clinics due to the cost and extra staff needed — though Magnus Medical has streamlined the training and brain-targeting processes. And many clinics will have to make adjustments to handle the 10 consecutive hours needed to accommodate the 10 treatments-per-day protocol.

In the meantime, Williams is casting a wide net in looking for new psychiatric tools, some unconventional. For example, in 2022 his lab ran a study to assess the use of ibogaine, a psychoactive drug, to treat 30 special operations veterans who have traumatic brain injuries and post-traumatic stress syndrome. (Ibogaine is derived from root bark and has been used for centuries by Africans in spiritual and healing ceremonies.)

Surprisingly, participants experienced average reductions in anxiety, depression and PTSD symptoms of 81%, 87% and 88%, respectively, with results that lasted throughout the monthlong study that was published in January 2024 in Nature Medicine. According to Williams, to date about 1,000 veterans have traveled to Mexico for this treatment — because this drug is illegal in the United States.

Williams sums up the history of psychiatry in this way: Psychiatry 1.0 focuses on your thinking, behavior and past trauma in a way that might keep you in therapy for the rest of your life. Psychiatry 2.0 affects neurotransmitter levels in your brain that might require you to take drugs forever. Psychiatry 3.0 refocuses the story on recalibrating your brain circuits, an approach that’s correctable with negligible side effects.

“I’m an agnostic psychiatric tool builder. If it’s safe for the patient and the risk-benefit ratio is right, we’ll look at it. My job is to find tools that can help people feel more like themselves.”

Where to get SNT treatments

The SAINT system for the treatment of major depressive disorder became available in April 2024. This integrated hardware/software system will enable medical clinics to set up their own treatment sites and benefit from ongoing research.

In addition, Magnus Medical will lead a four-center inpatient SAINT study of hospitalized patients with major depressive disorder and active suicidal ideation, with funding from the National Institutes of Mental Health. This double-blind study will evaluate how SAINT changes brain circuits and how these changes may affect suicidal thoughts.

The Brain Stimulation Lab is also running clinical trials for adults with major depressive disorder, bipolar disorder, borderline personality disorder and OCD.

For Gonzales, the restart of SNT treatments — and his research career — can’t begin soon enough. Though he’s anxious about how he’ll pay for the treatments, it’s been a life-changing experience for him.

“I spent so many years trying hard to get better with psychiatrists and drugs that didn’t work, but when they put a magnet on the side of my head, it magically made me better,” he said. “What’s liberating is that it showed me that depression doesn’t have to be my identity — it’s just a function of my brain biochemistry that can be fixed.”
— Contact Kris Newby at medmag@stanford.edu