Nolan Williams, MD, on the SAINT Depression Trial



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Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), a form of transcranial magnetic stimulation (TMS), reduced severe depression symptoms in 90% of participants in a small trial, researchers reported in The American Journal of Psychiatry.

Dr. Williams is an Assistant Professor in the Department of Psychiatry and Behavioral Sciences and Director of the Brain Stimulation Lab at the Stanford University School of Medicine in California. He has a broad background in neuropsychiatry and is double board-certified in both neurology and psychiatry. In addition, he has specific training and clinical expertise in the development of brain stimulation methodologies under Mark George, MD.



My name is Nolan Williams. I'm an assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University. I'm trained as both a psychiatrist and a neurologist.

There are neuroscience and clinical pragmatic reasons to do this sort of an approach and they kind of were aligned. The clinical pragmatic reason is that we don't have a rapid-acting TMS approach.

The current TMS approach takes at least 6 weeks for most people to start to really make a major impact in their depression. There are some data to suggest that you might need to go out to 12 or more weeks in people that are particularly severe.

The general issue with inpatient psychiatry, right now, is that unlike the rest of medicine, as you increase the acuity of psychiatric care, you reduce the number of options that people have, as far as, treatment outside of the context of the obvious increase in psychotherapy services.

As far as, the things that you can get as an inpatient versus outpatient for psychopharmacology, and for somatic treatments, interventional treatments, the options go down as a generality. If you're admitted to the psych hospital, you have a 10% chance that your psych hospital actually has electroconvulsive therapy. And 90% of US hospitals don't even have it.

A lot of people that could have gotten even ECT as an outpatient aren't able to get it as an inpatient. There's no TMS as an inpatient. There's no real consistent way to get IV ketamine or esketamine as an inpatient.

You're really left with the same medications that are available outpatient and the enhanced psychotherapy and protective aspects of an inpatient mission. What we tried to do, we're trying to develop SAINT, which is the Stanford Accelerated Intelligent Neuromodulation Therapy.

The idea from a clinical pragmatic standpoint behind that is that, if only 1.5% of people that meet Medicare/Medicaid criteria to receive ECT actually get it in the United States, that 98.5% of people, when they go into the hospital don't have that option, and we develop a TMS approach. It was a rapid enough TMS approach that could be condensed down to the time frame of somebody's inpatient psychiatric admission.

We've actually treated—this hasn't been published yet—but we've actually treated people who were admitted for suicidal depression in the inpatient service at Stanford. The goal was to show, in an open‑label way, just to show that it was feasible to do this.

It appears to be feasible to where you can actually bring somebody in, who's acutely depressed and suicidal. You can apply the SAINT protocol to them over the course of 5 days. They lose their suicidality, their mood improves, and they're able to be discharged within roughly 7, 8 days of the entire hospital admission, and they're walking out doing better.

That's the motivation on the clinical side. On the neuroscience side, TMS is never…no researchers have really done a dose response curve with it. We've done that with medications forever. Every medication that we have in psychiatry, we've given a range of doses, we find out what the side effects are, and then we figure out what the optimal dose is.

With TMS there's been some dose-finding work, but it's been in a very narrow range. Really, what we've done is we've pushed it in a very aggressive increase in dose over short period of time. What we see is it seems to be perfectly safe to do that. We've had no seizures, so far, we had no cognitive problems at all.

If anything, people's cognition is better. We're actually able to condense a 6‑week course of TMS into each day that people get treated.

Study Design and Findings

This was an initial phase I signals of safety and hints of efficacy study. The goal of this study was to run a little more than 20 individuals that had treatment‑resistant depression and determine is this level of stimulation, is this amount of stimulation safe to do.

We identified those individuals. We do a resting‑state functional connectivity MRI scan and a structural scan of their brain before they come in to get treated. Then we built software that finds an ideal position for the coil in each individual's brain.

That information gets put into the software that we have in the TMS treatment room that is stereotactic software that people use for TMS. They also use a version of this thing for stereotactic brain surgery. It's a very accurate way of positioning things outside or inside the head, in this case outside the head.

We were able to position a coil superimposed over the ideal spot, and then we were able to apply the SAINT protocol. Like I said, it's a 6‑week course of intermittent theta‑burst each day worth of dose, so it's 1800 theta‑burst pulses, about 9 minutes every hour for 10 hours.

By the end of that day (they come in around 7 and leave around 5), they've gotten a whole course of TMS. We had a few people who remitted at the end of the first day, and we continued to do that for 5 days, from Monday through Friday. By Friday, 90% of folks were feeling better, and we followed them out for several months out.

The overall efficacy was quite surprising to me. That was maybe the most surprising bit about it, was that we were really surprised that we saw such high numbers. We suspected that we could speed it up. There was a lot of data to suggest that, but there wasn't the data to suggest that you could get this many full well.

Clinical Applications

The most near‑term thing is that we're going after trying to get feedback from the FDA and hope to eventually get an FDA approval for a new billing code to do this sort of TMS.

I think that there's a whole lot of settings in which this could be quite useful—emergency rooms, inpatient psychiatric hospitals, partial hospitalization programs, and intensive outpatient programs.

The stimulation's only 10 minutes per hour, so in theory you could build intensive outpatient programs, partial hospitalization programs, where there's stimulation and therapeutic programs interdigitated to get people well and give them the psychotherapeutic tools to do it, and then help to restore some of their brain function at the same time.


Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for treatment-resistant depression. The American Journal of Psychiatry. 2020 April 7;[Epub ahead of print].

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