- Welcome to "Healthy Minds" I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one, do not suffer in silence.

With help, there is hope.

Today on "Healthy Minds".

You're taking what is already FDA approved, which is transcranial magnetic stimulation, and you're fine-tuning that so that it could be individualized to specific people.

And that you can do it more rapidly, you can give more treatments in a shorter period of time.

And you're giving a stronger dosage of treatment with each of those treatments to get a rapid response to that treatment.

- That is correct, we're utilizing an FDA approved device, but we're using it in a very different way.

We've seen folks get well in as little as a day and, you know, a lot of people well by the fifth day.

- That's today on "Healthy Minds".

This program is brought to you in part by the American Psychiatric Association Foundation, the Bank of America Charitable Gift Fund, and the John and Polly Sparks Foundation.

(soft bright music) Welcome to "Healthy Minds" I'm Dr. Jeff Borenstein.

It's not that often, in psychiatry or all of medicine that we see a potential game-changer in treatment.

Today, I speak with Dr. Nolan Williams, who describes his work on such a potential game-changer.

(soft bright music) Nolan, thank you for joining us.

I appreciate your being here virtually, 3,000 miles away, but the next best thing to being here in person.

So, thank you for being with us.

- Yeah Jeff, thanks for having me and thanks for the interest in the work we're doing.

- I wanna jump right into that work because it's very exciting and can have a tremendous impact on clinical treatment.

So, tell us about what you're doing.

- We've termed this Stanford Accelerated Intelligent Neuromodulation Therapy.

And the idea is that we can reorganize the stimulation involved in repetitive transcranial magnetic stimulation so that it's applied in a different way in space, in time, and in dose.

And so, the space piece is that we're utilizing personalized neuroimaging based off of an individual's functional neuroanatomy to place the coil in the best spot for their brain, to stimulate.

And the second bit is, that we're reorganizing the stimulation in time.

So, this idea that we can apply a whole lot of stimulation in a short period of time.

So, we can actually apply a six week course of conventional RTMS worth of stimulation, in a single day.

So, the way that we typically apply something called intermittent theta burst stimulation, which is this new form of stimulation that can be applied, you know, over a six week course.

We can do that in a single day and give the same dose.

And then the third innovation is, this ability to do a dose response curve with RTMS.

So, we can actually apply, you know, five times the amount of stimulation that's normally applied in six weeks, in five days.

And we are able to get, you know, a much larger percentage of folks well in that short period of time.

So, it's really those three innovations.

- So you're taking what is already FDA approved, which is transcranial magnetic stimulation.

And you're fine tuning that so that it could be individualized to specific people.

And that you can do it more rapidly, you could give more treatments in a shorter period of time.

And you're giving a stronger dosage of treatment with each of those treatments, to get a rapid response to that treatment.

- Absolutely, so yeah, that is correct.

We're utilizing an FDA approved device, but we're using it in a very different way than any of the previous trials have utilized this device.

So, we're really using it in this rapid kind of personalized way.

And I think that's, you know, that's probably part of the ingredient to why we're seeing such both, a robust effect and a very rapid ones.

We've seen folks get well in as little as a day and, you know, a lot of people well by the fifth day.

And so, that's been the observation so far.

- Let's take a step back and just explain, how does this work?

How does using magnets to the head, how does that work?

- Absolutely, so you know, we've known for a long time a principle called Faraday's law, where if you pulse a magnet you can generate a current in electrically conducting substances.

And so, that principle's been around for some time.

It was first tested by Tony Barker in 1985 in humans and published in "The Lancet" then.

And so, you know, our moves here were to really take that to the next level, and really be able to personalize it.

And really, you know, utilize the neuroscience that's emerged over the last 20 years around how the brain learns, to really extend this approach to a larger group of people.

And there hasn't been, prior to our work, there hasn't been a, you know, a strategy to do this in kind of a blinded prospective way where you're giving a certain amount of stimulation over a period of time and then you're looking at behavior change.

So, as all the pharmacologists know, what you wanna see, is you wanna see escalating dose in a flattening or plateauing of the curve.

So, then you have a sense of, "Okay, if I give more dose here, I'm not gonna necessarily improve behavior."

"And then I may, you know, in the case of drugs, increase risk."

And what we observed is that if you look at the FDA approved dose, that's been approved for intermittent theta burst, it's only the first day of stimulation for us.

And we see a certain percentage of folks that get better after that first day.

But then, the subsequent four days, we're giving, you know, accumulation of a total of five times the amount of stimulation that we give with an FDA approved treatment course.

And so, that allows us to really try to get a sense if we give more dose, do we pick up more and more improvement over time?

And, that's what we've observed.

We've observed that as you treat people with more and more pulses, you pick up more and more remitters as you go further and further into that week.

And, that's been an interesting kind of third dosing principle.

And so, you know, these three things seem to be important for its effect.

You know, if you cut the dose short and you only give a day, for instance.

You're not gonna give, you're not gonna get the level of improvement that we see across the board with folks after five days.

If you do the spacing, you know, we did some early piloting with different spacing.

If you do the spacing at a non-optimal level, then you don't get the same clinical effects.

And so, you know, we have a sense that it's really this set of ingredients that allows for this level of efficacy.

- And in your preliminary work with this, you're finding a very high rate of response much higher than with typical medications, and much higher than with the more traditional uses of transcranial magnetic stimulation.

- Absolutely, so what we've observed is, if you look at the end of the first day, that's the dose of the, you know, equivalent dose of a conventionally applied theta burst six weeks, and you get about the same numbers.

But, if you keep going, then you pick up more and more responders and remitters as you get deeper into the five days of the treatment week.

And so, that suggests, you know, a potential under-dosing, historically.

Which is, you know, that's what we've observed, and if other people observe the same thing too, it's great news, right?

'Cause TMS is exceedingly safe, and that's just a suggestion that maybe we've been a little bit too safe.

In reality, it's quite safe and you can give this these higher doses, and people do quite well.

- And part of what's so exciting, in addition to the response rate, is how quickly people are able, people respond to the treatment.

Talk a little bit about that as well.

- Yeah absolutely, so, we've observed folks, you know, achieve benefit anywhere are from one to five days.

The younger, less treatment-resistant folks that we've treated, you know, two, three, four med failures instead of 10.

You know, you start to see those folks get better at the end of the first day or two days.

And it's really dramatic, and it's really exciting.

You know, there's not a neuromodulation treatment that can do this, in this short period of time.

Certainly ketamine can have this level of speed.

We've observed, you know, decently good durability on this as well.

And so, it's nice in the sense that we have, you know, relatively rapid acting approach that seems to stick around for a while.

And, I think that that's really exciting.

So, we can get people out of psychiatric emergencies in a very short period of time, and get them back and well.

- So.

- And back out of the hospital.

- So, this is for, certainly, when I went to medical school and residency, when you went to medical school and residency, the idea of a treatment that could act so rapidly, we didn't even think that was possible yet.

But this is- - Yeah.

- Truly a potential game-changer in the treatment of acute depression and suicidal risk.

- Absolutely, yeah, I mean I think the beauty of the ketamine work that's been done so far is that I think the field got to see that, yes, we can actually see depression change this fast.

And, you know, that aspect of ketamine really inspired thinking about this.

You know, in a similar sort of vein, you know, we see folks get well in timeframes that we normally don't think folks can get well in.

And it's really exciting.

And I think it speaks to the idea that we're tapping into kind of the central mechanisms around mood regulation.

You know, one way of thinking about this is, this is a rapid acting treatment to treat psychiatric emergencies in settings that we haven't really had, consistently had a treatment in.

The other way to think about it is, well, we've got a probe that's non-invasive that seems to work in a broad range of folks.

We've seen it work in, even in people that have failed electroconvulsive therapy.

And so, as a probe and a neuroscientific tool, it's really exciting 'cause it feels like it's something closer to kind of a complete probe.

We can really perturb the brain circuitry of a wide range of people and we're ethically justified to do so, because the risk-benefit ratio is so on the benefit side of things.

And so, being able to use it as a probe, ask the questions of what does this probe do in less treatment, and in more treatment resistant folks?

How do the brains differ?

How do the brain responsivity differences, what are reflected in the differences in the brain responsivity to this probe?

So, I think that's another exciting aspect of this work, is being able to say, "Okay, we've got a probe we can really explore things with."

- I want you to talk a little bit about side effects that people may have experienced with this treatment.

- Side effects, yeah so one of the side effects that is kind of the predominant one that we saw was different between the, you know, it wasn't statistically significantly different, but different, you know, at a level between the two groups, was the rate of headache.

It didn't seem to really affect the blind at all.

These were all mild headaches.

They were all Tylenol responsive and lasted a few hours.

But the folks in the active group had, you know, slightly more headache.

Other than that, we really haven't seen much.

You know, I was very conscientious to the idea that we were gonna have to convince folks that this was cognitively okay to do, right.

You're giving this much stimulation in a day, you have to justify that the risk for doing this is not really, is marginal and not really there.

And, that's what we observed, right.

If anything people's, you know, certain domains of patient's cognition actually improved.

A lot of cognition actually stayed the same.

There were no patterns to say that it worsened at all.

And, that's a big deal in contrast ECT, where there known, you know, neuropsychological effects of ECT on the kind of autobiographical memory for some people.

And so, that's a contrast there.

And then the other piece is, folks generally worry about seizure.

They worry about seizure as it relates to, you know, to TMS.

Because in the early days, before we knew what we know now, there are a couple of seizures that happened.

Subsequently, it's been a very rare event.

And a lot of it's been due to operator error, in conventional RTMS.

In our hands, we have yet to see any seizures with this approach.

Which is also great news.

And so, in more than 100 people, we've not observed a single seizure, in individuals receiving this.

And, you know, it appears to be, you know, exceedingly safe in that way.

And so, no seizures, no cognitive issues.

And the rest of the side effects they're, you know, adverse events that we saw in the trial.

In the randomized control trial, both groups had it.

So, fatigue, you know, we observed a specific type of a fatigue that people talk about.

They didn't see as being really related to their depression at all, but just being there all day.

You know, both groups experienced that.

These are long days.

People sleep off some of that fatigue on a Saturday, after their Monday through Friday course, and then they're feeling great.

You know, if they got active and they're doing well, you know, early that next week.

And so, that's something to know.

You know, and that's really the, some people have some sensitivity to the nerve effects of the TMS as a generality, not specific to this.

But, really that's it.

So, it's in the scheme of things, with everything that's being explored right now as potential treatments for people with treatment resistant depression, it's side effect kind of risk-benefit ratio looks really good.

- And I want to emphasize what you just said, which is these are treatment resistant depression patients, These are people who have tried other things, a few different medicines, other types of treatment, and it didn't work.

And for these people who have this kind of response, it really changes their life.

They're for the first time in many years, they're feeling well.

- Absolutely, yeah, that's a great point.

So really interesting, you know, group that we just published on in our randomized control trial, really sick folks, very unfortunate group of people who, about 50% of them were actually disabled from depression.

And their average length of their current depressive episode, how long they've been depressed, you know, know kind of continuously in time for this last episode, was around nine years.

You know, these were people who were not even typical conventional RTMS trial participants.

These were sick, sick patients.

Patients that, you know, in doing ECT over the years, are really outpatient ECT patients, right.

And, you know, both in level of treatment resistance, and current severity, and all of that.

And, you know, it had some really exciting, really dramatic improvements in these folks lives.

And, you know, for a good bit of the folks that got active, really transformative for quite some time for them.

- And you said that it lasts.

- You know, we do... - What do you do for ongoing care to maintain their response to the treatment?

- Yeah, that's a great question.

So, you know, our first trial participant, you know, knock on wood, I think he's still well.

Last time I checked in with him a couple of months ago, he was still well at four years.

We've had folks who've lost it quicker than that.

You know, on average, it's a couple of months the... You know, we've had a few folks with, that have failed electroconvulsive therapy are quite severe individuals, kind of the furthest on the bell curve of severity.

Those individuals need, you know, an aggressive kind of SAINT-style maintenance stimulation, where they're getting, you know, more stimulation throughout the day.

What's interesting is I think you can treat somebody that's very early in the treatment algorithm.

You know, we've done this with quite severe folks in the inpatient unit that came in after a suicide attempt, were very ill, but not particularly treatment resistant.

You know, and they get, you know, very durable effects as a generality.

Some folks that need maintenance, and then we've been thinking about how do you do this with an implanted cortical stimulator?

And do the same sort of stimulation patterns, direct electrical, instead of induced with a magnet to really treat people ongoing that need really frequent stimulation.

And I think that's kind of the, mental model is that we, you know, it's not just a TMS approach, but this is a neurostimulation approach for stimulating cortex that is really a platform technology across a lot of potential modalities.

And that's one of the things I'm most excited about.

That we can potentially keep the whole range of folks well that are responsive to this.

- In addition to treating people with depression, what other conditions do you envision this being helpful for?

- Absolutely, so a group of us worked on obsessive compulsive disorder.

It was a small pilot, but three out of seven of those patients with treatment resistant OCD crossed the remission line, Y-BOCS less than 10, the Yale-Brown Obsessive Compulsive Score.

And that's really exciting 'cause as you know Jeff, these folks, remission's not a term that's utilized very frequently in OCD circles.

And so, to see that sort of improvement's really great.

We've had foundation funding to look at this in borderline personality disorder, and folks with BPD and depression.

Some funding to look at bipolar disorder, both mania and depression.

And that initial work, you know, has helped to be prelim data for multiple funded grants going forward, looking at both major depression and bipolar II.

And so, you know, and in addition to looking at this in outpatients, we did some piloting kind of feasibility work with inpatients that were suicidal.

And now the NIH has been generous enough to fund a randomized control trial of about 100 individuals, here at Stanford, to assess the effects in suicidal, actively suicidal folks.

- So, really understanding some of the very basic science of how the brain works, and what parts of the brain may be affected by different conditions, allows these clinical interventions aiming at the specific part of the brain, the circuits in the brain, that may have caused depression, OCD, some of the other conditions.

- Absolutely, yeah, I mean the basic and translational work that's been done over the last three decades, you know, it was essential to understanding what we needed.

What pieces of this engineering puzzle we needed to put together to make this work.

And it was really a, you know, initially an engineering experiment that, obviously, when we did some science and did a randomized control trial on, it was really utilizing the basic and translational neuroscience over, you know, really since the 80s and 90s, all the way 'til when we started working on this, you know, around 2015, 2014, to put this together.

And without that work, and without, essentially, federal funding, and funding from foundations, like NARSAD, you know, I don't think that this sort of clinical innovation would be possible.

We wouldn't have known what to do, without that kind of basic information to guide us.

- Nolan, let me ask you, where do you see this going over the next 5, 10, 20 years?

Where do you see this work leading us to?

- I can see a future where someone with suicidal depression comes in the emergency room at some point gets an MRI scan, at some point gets set up to receive, you know, this stimulation or some next generation version of this.

And that, you know, allows for them to achieve remission response to suicidal depression, elimination of the suicidal behaviors and thoughts.

And then they can leave the hospital, you know, in a safe way.

That's in contrast to the current scenario where in people that are admitted to psychiatric hospitalization for their first mood disorder episode, their risk of completed and attempted suicide in the three months after that hospitalization is the highest, lifetime.

And, you know, a future, a particularly optimistic, hopeful future of mine is that we would be able to see that, right.

That people would come into the hospital for suicidal depression exactly once.

And that we would be able to, in a lot of those people, maybe not everybody, but in a lot of those people, we would be able to maintain them with these sorts of protocols or versions of these sorts of protocols outpatient, and turn this into a similar sort of setting.

And so, it's a big dream, you know, who knows if we can pull it off.

And, you know, there's a lot of work to be done, but I think it's an important one.

It's one that if the field could get there, it would change a lot of lives.

It would change the way that we think about this particular illness and hopefully related illnesses that we think we can have an effect on with this technology.

And, you know, hopefully make it a safer sort of scenario for folks suffering from this.

- Well I agree with you, it's a big dream, but the only way you have big advancements is with a big dream.

And the idea that somebody could be acutely suicidal with depression, and have a quick response to treatment that continues to stay, that so the depression and suicide risk stays in remission, is a game-changer in our field.

So, a person doesn't need to stay in the hospital for a few weeks until the depression and suicide risk lifts.

They could go home after a few days when it lifts, and then have ongoing treatment.

So, it's a dream that really is a game-changer and your work is helping to make that dream potentially come true.

- Yeah, thanks Jeff.

Yeah, we hope so.

I mean, I think that's definitely, you know, I'd love for that to be the case, if it did.

- Nolan, I want to thank you for all the work that you've done, for joining us today to share that.

And, just as importantly, for the work that you're going to do in the future, that will have such an impact on so many lives.

- Thanks Jeff, yeah, it's an exciting time and really appreciative of all the different funding agencies that support basic translational and clinical neuroscience research.

It really makes a big difference and allows for us to develop these sorts of treatments and explore what needs to be explored to kind of improve the field, and improve the lives of folks suffering.

- Thank you so much.

Look forward to seeing you in person, in the very near future.

- Sounds great, thanks Jeff.

(soft bright music) - As a psychiatrist, I'm truly inspired to hear about people who have treatment resistant depression finally get help, get better.

It demonstrates that through research and advancements in treatment, with help, there is hope.

(soft bright music) Do not suffer in silence.

With help, there is hope This program is brought to you in part by the American Psychiatric Association Foundation, the Bank of America Charitable Gift Fund, and the John and Polly Sparks Foundation.

Remember, with help, here is hope.

(soft bright music)