Interventional Approaches to Treatment-Resistant Mood Disorders

Joshua Berman, MD, PhD, discusses how careful evaluation, patient priorities, and risk-benefit tradeoffs guide the use of interventional treatments when conventional approaches fall short. Dr. Berman also explains how tools such as ketamine, TMS, ECT, and neurofeedback can be used strategically—sometimes in sequence or combination—to address different vulnerabilities within mood-related brain circuits.

Dr. Berman is Associate Professor of Psychiatry and Director of Interventional Psychiatry at NYU Langone Health.

Topics

• Evaluating patients who have not improved with medications or psychotherapy
• The limitations of existing treatment guidelines for complex cases
• When and why sequencing or combining interventions may be appropriate
• Emerging approaches such as EEG-guided neurofeedback and focused ultrasound
• Building a comprehensive, patient-centered interventional psychiatry program

This episode offers a clinician-level perspective on how interventional psychiatry is practiced today, and how new technologies may expand options for patients with the most challenging presentations.

Chapters

00:00 Introduction: Caring for Patients Who Don’t Respond to Standard Treatment
00:47 What Is Interventional Psychiatry?
02:33 Evaluating Treatment-Resistant Presentations
06:31 Precision, Patient Priorities, and Clinical Judgment
09:35 Sequencing and Combining Interventions
10:40 Limits of Treatment Guidelines
12:18 The Future of Interventional Psychiatry
13:23 Emerging Technologies: Neurofeedback and Focused Ultrasound
17:15 Building a Comprehensive Interventional Program
18:13 Tools vs. Understanding Brain Circuits

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Senior Producer: Jon Earle

Transcript

[00:00:00] Joshua Berman, MD, PhD: Almost everyone comes in saying, "I've tried everything," and they haven't. It's important for them to know that you have to help patients overcome what, at that point, may be their own hopelessness.

[00:00:13] Charles Marmar, MD: Right.

[00:00:13] Joshua Berman, MD, PhD: One of the things we're interested in in our program is, can you sequence things, even things that have already been tried, would they work after something else? You know, the atmosphere of the brain has changed because of something you did. They may not be all better yet, but then you bring back something else, and that may bring about further improvement.

[00:00:36] Charles Marmar, MD: Welcome to Insights on Psychiatry. I'm your host, Dr. Charlie Marmar, Chair of the Department of Psychiatry at NYU Grossman School of Medicine. Today, I have the pleasure of speaking with Dr. Joshua Berman, who is an Associate Professor in our department and directs Interventional Psychiatry for NYU Langone Health.

So, Josh, the focus of our podcast, broadly speaking, is on understanding how to care for complex psychiatric illness, particularly the patients that are diagnostically challenging and don't necessarily respond to the kind of normal pathways for evidence-based care. 

Joshua Berman, MD, PhD: There's a whole range of levels of invasiveness and precision in location.

If we go over to the pharmacological side, we're talking about things like ketamine and esketamine, and someday, I think, the psychedelics. Those become interventional because the patient is in an altered state during the treatment. Here, I'd say, is the interventional approach, and it's true for neuromodulation as well.

It allows us to go outside of what we normally do by carefully timing targets, timing intervention, when we do interventions, and having medical supervision for the interventions. We can do things that are beyond just what you can do when you prescribe a medication or do psychotherapy.

Charles Marmar, MD: Perfect. So you've had 25 years of experience and have been a major leader of interventional psychiatry in New York and your previous work at Columbia before we were very fortunate to recruit you to NYU Medical Center. In your experience, if you were to discuss a composite case, briefly—not to disclose, obviously, we're very sensitive about patient privacy in all of medicine, especially in psychiatry—

but if you think of a composite case of someone who's complex and has had difficulty, even though there's been a number of efforts to care for them, what would that case look like? What would their typical history be? And how is interventional psychiatry a new answer to an old problem?

[00:03:12] Joshua Berman, MD, PhD: So, you know, it really starts with good evaluation. The idea is you want to understand how that patient got to the point where conventional treatments are not helping them. And, by the way—whole other discussion—there may be instances where we're too hesitant to bring in interventional approaches, and there may come a point when we start to bring them in much earlier in the treatment algorithm.

But right now, usually patients have tried a few different medications, maybe one or more modes of psychotherapy, and they're stuck. They're either stuck because they've been ill for a long time and haven't gotten better, or because they're having repeated bouts of illness and whatever they're taking—maybe they get better briefly, but it doesn't hold them. So you do a good evaluation. You want to know, one, what's the pattern of their illness, and are there pieces of the picture— maybe there's occult bipolarity. Maybe there's a comorbidity that nobody has paid attention to and needs to be addressed in a different way.

You want to know what treatments have been tried. Often, there are holes in the psychopharmacology. We don't do an interventional treatment for everyone who comes to us. Sometimes we say, "You didn't try this. There's a particular class or combination of medications or a particular kind of therapy."

So you want to understand what their treatment history has been. You actually want to get a thorough medical history because that may determine what interventional treatments are going to be least risky for them as opposed to most risky. There are specific questions you ask that have to do with each particular interventional treatment. You know, like seizure risks for TMS or blood pressure-sensitive lesions for ECT, things like that. Then you have a stage where you talk to their therapist and their psychiatrist. I believe it's really important, as an interventionalist, to involve the treatment team and to create a sort of continuity in the patient's care.

Interventions are time-limited, and then they're going to go back to their regular treatment and be maintained in some way. We try to then work with the patient to get a sense of what their priorities are. Because right now, unfortunately, I can't tell you which treatment is going to work.

There are two things, though, that happen. One is almost everyone comes in saying, "I've tried everything," and they haven't. It's important for them to know that you have to help patients overcome what, at that point, may be their own hopelessness and desperation. You don't want somebody going into a treatment thinking, "This is my last hope," because it almost never is.

And I'll get to that. Even things you've already tried—one of the things we're interested in in our program, is: Can you sequence things, even things that have already been tried? Would they work after something else? The atmosphere of the brain has changed because of something you did.

They may not be all better yet, but then you bring back something else, and that may bring about further improvement. So you get a sense of where they are in terms of their expectations for treatment. You have to understand what's their biggest concern. Some people want to go with the thing with the highest response rate first.

Some people are more concerned about managing risk and want to do the least invasive thing first. Some people are looking for speed and want to do the fastest treatments first, and some people are looking for durability. They don't want to be tied down to something that has a long maintenance period if possible, so they want to do the thing that's most likely to last.

[00:07:10] Charles Marmar, MD: So when you think about the broad field of—the emerging field of precision psychiatry, as we move to be closer to the very high standard of care in oncology or cardiology, where each patient with breast or prostate cancer receives a genomically informed, personalized treatment—we're not there yet in psychiatry—but you're raising an interesting point, which is: Precision medicine means not just the ideas the doctor has, but precisely understanding what makes sense to a patient.

[00:07:51] Joshua Berman, MD, PhD: Exactly. The patient's expectations, fears, and hopes during a treatment are really important and, in our field in particular, have a big impact on outcome.

The precision point is interesting because I think we have a bigger challenge than many other fields in that a lot of the time we're treating syndromes and we're not yet sure what the structure of those syndromes are. You look at heart failure—there are a number of discrete different causes with a final common pathway.

If somebody's in pulmonary edema, you do the same thing no matter what, but then you go in and figure out why they are in heart failure, and you try to address that. We may not have exact categorical causes. Our precision medicine may turn out to be very different because it may be a spectrum of underlying causes coming together.

That is one of the things that makes me interested in combining interventional treatments in sequence, which is something we haven't done that much of, but we're starting to think about. The idea being: Patients have many different vulnerabilities that predispose them to developing an illness.

I mostly focus on mood disorders, so I'll just use the example of depression. We think about a failure of pathways that support neural connectivity in the limbic system, which is the behavioral and emotional system in the brain. Another category would be—failures in what I call the switching neurons, the big inhibitory interneurons that are like the conductors. There's probably lots more, but we know of many different ways that people may be vulnerable to having problems in these circuits. The thing is, they can have more than one.

So a particular treatment may rely on going through a functional pathway to a certain point. They may have something that blocks that, so that may mean you have to fix one thing with one mode, and then you have to come in and fix something else with another mode in order to get those last group of people to be responders and remitters.

[00:10:14] Charles Marmar, MD: For example, if someone has difficult-to-treat refractory depression, you might have to tune up their medications, augment their antidepressants with thyroid or lithium or something else, a neuroleptic, and then think about TMS with that.

[00:10:33] Joshua Berman, MD, PhD: Right. There's even starting to be hints—there's a small group of people who don't respond to ketamine, don't respond to ECT, but if you alternate the two, they do better. That, to me, says there's more than one box that's locked with the key in it. You have to do something—for you have to unlock the boxes in the right order, get the keys out, and unlock the next box.

[00:10:55] Charles Marmar, MD: I think that becomes, in some ways, the art of complex treatment as well as the science. The field has so-called treatment guidelines, which are very hierarchical and prescriptive, but don't address the complexity you're mentioning. How do you see the limitations of treatment guidelines when you think of interventional treatments for depression?

[00:11:19] Joshua Berman, MD, PhD: You raise an interesting point. One of the interesting points to me is that interventional treatments differ from other treatments in that they have more degrees of freedom. 

When you have a medicine, if you look at the half-lives of medicines, basically there's dose and maybe how frequently you take it, and you're going to reach a steady state, and that's that. Those are the degrees of freedom. When you're doing an interventional treatment, particularly a neuromodulation treatment—

You've got amplitude of the stimulus, location of the stimulus, pulse width, frequency. That's not to mention how many times a day or a week you do the treatment, how many in succession, when do you stop, when do you taper. It's almost impossible to test those things in the framework of clinical trials that we have.

People pick what they think is going to be the best combination of all those things, and they test it against some kind of sham treatment. They have a built-in measure of whether—usually it's whether people think they're getting sham or not. If they're not better than chance, then your sham worked.

Um, but you test things that way, but there's very limited—you know, we don't have enough universes to test all the possibilities. So the guidelines that exist are important, they're reasonable, but they're also based on very limited information. Sometimes you have to have ways of going a little bit outside of those guidelines, but you have to think about how you do it.

You can't just be, you know,—a cowboy. So—

[00:12:57] Charles Marmar, MD: We don't have three parameters to vary; we might have a hundred parameters— 

[00:13:01] Joshua Berman, MD, PhD: Exactly 

[00:13:02] Charles Marmar, MD: —to vary, and that's part of the complexity. Ten years from now, what kind of really cool new ideas will there be in intervention that you'll be—like, for example, ultrasound or other things—that will change our field?

Joshua Berman, MD, PhD: You mentioned ultrasound, which is potentially one that allows modulation. Because of the nature of ultrasound, you can actually reach deep targets in the brain, which you can't easily reach with TMS unless you use deep TMS, but then you lose specificity. Ultrasound gives you specificity and depth, and that can modulate circuits.

The other interesting thing about ultrasound is that it locally opens up the blood-brain barrier a little bit and may actually allow brain markers to circulate in a way that we can assay them, so that we could get localized biochemical information about brain regions of interest noninvasively.

So that's one thing. I think our ability to guide the treatments we have, like TMS or ultrasound, will improve as we get scalable markers that are devised from brain imaging. What I mean by that is, the best brain imaging markers are from resting-state connectivity measurements in fMRI. That requires somebody to sit in an fMRI for 20 minutes or more.

Then the data has to be crunched. Although I think over time there'll be better ways to do that with automation, it's still not the most scalable thing. But I'm going to take the example of Prism, which you're very familiar with. It's an EEG-guided neurofeedback technique. And it's part of our armamentarium now. The people who developed Prism used fMRI data, but then they managed to correlate it with an EEG signal that's very easy to acquire with very inexpensive equipment. What that allows is scalability. The ideal is to have things in a doctor's office that they can personalize your treatment with. Another one is fNIRS—that's functional near-infrared spectroscopy.

That's sort of like having a little brain imaging module in your office. Now right now, it's not quite that scalable, but people are working on fNIRS units. Imagine I'm doing TMS, I put down an fNIRS unit on one part of your head, and I'm doing the TMS on the other, and I look at it and say, "Oh, we're not getting quite the signal we need," and then I move it. That kind of thing is coming.

Charles Marmar, MD: So fNIRS is an MRI in a box. 

Joshua Berman, MD, PhD: It's moving in that direction. It might become one. 

Charles Marmar, MD: By the way, on the Prism neurofeedback, Dr. Talma Hendler developed this in Israel and had the idea, which was—some other investigators also—to simultaneously acquire EEG while the patient's in the magnet so you could find a simple EEG signal to correlate with that. And then you can do that work in a private-practice office. 

[00:16:28] Joshua Berman, MD, PhD: And now that signal is used to power the virtual-reality computer program that the patient interacts with in the neurofeedback, where they learn to enhance activities that are therapeutic for anxiety, trauma, or depression— 

[00:16:46] Charles Marmar, MD: For example, to exercise the brain circuit of emotion regulation. 

Joshua Berman, MD, PhD: Exactly. 

Charles Marmar, MD: And cool down their amygdala, which is—now we're thinking about the future of psychiatry, which is—

[00:16:59] Joshua Berman, MD, PhD: By the way, those signals can probably be acquired and used in other treatments. If the patient doesn't happen to respond to that treatment, those signals still may be useful.

[00:17:08] Charles Marmar, MD: So we do offer TMS. We do offer ketamine. We do offer Prism neurofeedback, and we will be offering ultrasound in the future in our program.

[00:17:19] Joshua Berman, MD, PhD: Yes. We're in the early stages right now of assembling everything, but what we're going to have in short order is a program that offers all the different modalities, all the way up to neurosurgical intervention.

Charles Marmar, MD: Right, for deep brain work. 

Joshua Berman, MD, PhD: I want to mention, I think it's important that we be comprehensive, rather than be TMS specialists or ketamine specialists, because I want us to be patient-centered. The patients may come in with a particular idea of, "Oh, I heard about this. I think it's interesting." And they're often right. The idea is to be able to present patients with a range of options. Also, if you have all these things, you can start to combine them. If you're only doing one thing, you can't really combine them. 

[00:18:07] Charles Marmar, MD: So, we're going to need to stop today, but we'll have you back. 

Just on a historical note about—is it the tool or is it the field? If the railroad barons at the end of the 19th century understood they were in the transportation business rather than the railroad business, they would have owned all the airlines, because they had all the capital. But they thought they were in the railroad business. So we don't want to be in the TMS business. We want to be in the understanding of the deep aspects of brain function that will allow us to use any set of tools in any safe combination to help the most complex patients.

[00:18:52] Joshua Berman, MD, PhD: I couldn't have said it any better.

[00:18:53] Charles Marmar, MD: Thank you very much. It's been my pleasure, Dr. Josh Berman, our newly recruited head and leader in interventional psychiatry. It's been a pleasure speaking with you. 

Joshua Berman, MD, PhD: Same here.