Treatment-Resistant Psychiatric Disorders

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: March 1, 2025
Expiration Date: February 28, 2026

Estimated Time of Completion: 30 minutes

Treatment-Resistant Psychiatric Disorders
Stephen Ferber, MD

Description
Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience
Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

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  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

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Podcast Series Director
Andreas Alexopoulos, MD, MPH
Epilepsy Center

Additional Planner/Reviewer
Cindy Willis, DNP

Faculty
Stephen Ferber, MD
Center for Adult Behavioral Health

Host
Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Treatment-Resistant Psychiatric Disorders
Stephen Ferber, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Glen Stevens, DO, PhD

DynaMed Consulting

All other individuals have indicated no relationship which, in the context of their involvement, could be perceived as a potential conflict of interest.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

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Introduction: Neuro Pathways: A Cleveland Clinic Podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro-rehab, and psychiatry.

Glen Stevens, DO, PhD: An estimated 30 to 50% of patients with psychiatric disorders battle with treatment resistance, contributing to higher healthcare, unemployment and productivity costs. Conversely, less than 1% of psychiatric research is conducted on treatment-resistant cases. In today's episode of Neuro Pathways, we turn our attention to the field of treatment-resistant psychiatric disorders, discussing the complexities of care, exploring innovative therapies and underscoring the importance of dedicated programs to improve patient outcomes.

I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to be joined by Dr. Stephen Ferber. Dr. Ferber is the Assistant Director of the Psychiatric Treatment-Resistance Program in Cleveland Clinic's Neurological Institute's Department of Psychiatry and Psychology. Stephen, welcome to Neuro Pathways.

Stephen Ferber, MD: Thank you so much, Glen. Really appreciate being here.

Glen Stevens, DO, PhD: So Stephen, tell us a little bit about yourself, your background, how you made your way to Cleveland, what you do on a daily basis.

Stephen Ferber, MD:      ure, absolutely. So I had a bit of a convoluted path here. So did my residency at Columbia and then fellowship in Interventional Neuropsychiatry and Neuromodulation at MGH. I took a job back in New York, and then around a year afterwards, my fiancé matched into general surgery in the Ohio area. So it was a bit of a forced move, if you will, but very, very grateful to Dr. Pozuelo and Dr. Barnett for bringing me on board.

Glen Stevens, DO, PhD: Well, we all come from a different path, right?

Stephen Ferber, MD: And this was mine.

Glen Stevens, DO, PhD: And we're happy to have you here. Where do you practice, mostly? Are you on the main campus? Are you in one of the satellites, or where?

Stephen Ferber, MD: Yeah, so they moved me down to Akron General. So since I've gotten here, the plan has been to expand interventional psychiatry throughout the system. And so the first stop on that path was south, and so we've kind of brought in Akron into the fold, and now we're trying to offer these treatments at as many sites as possible.

Glen Stevens, DO, PhD: So we're talking about treatment-resistant psychiatric disorders. I guess what we should do first is just define treatment resistance.

Stephen Ferber, MD: Sure, I wish I could do that for you. And this is something that-

Glen Stevens, DO, PhD: I asked you to.

Stephen Ferber, MD: So I mean, I don't know this for a fact, but I can't imagine that at nephrology annual conferences, they're pounding the table, debating what constitutes stage three CKD. They agree, right? Psychiatry isn't there yet. And so country to country, hospital to hospital, or even practitioner to practitioner, you're going to get a different definition of what exactly treatment resistance is. And that also depends on the condition that we're talking about, most commonly treatment-resistant depression or TRD. But our consensus has not been reached across the field, which has led to a lot of problems in terms of access to care when patients get referred to us.

But ballpark, the most common definition that you will see, and I'll use TRD as an example, is after two failed adequate trials of a medication, a psychopharmacological intervention, we typically then define the individual as having treatment-resistant depression. The reason for that, one of the better designed studies called STAR*D looked at antidepressant response rates, and whether there were optimal switching strategies or continuation strategies, should someone not achieve remission. And what they found is that, completely independent of what the treatment offered was, if you have failed two medications, your chance of achieving remission with a third strategy was less than 15%. And so that's kind of where we have this cutoff of now you've entered into the realm of TRD.

Glen Stevens, DO, PhD: And it's really a little bit like the epilepsy field, where now they say if you failed two adequate trials of the medication and you're still having seizures, then you're probably resistant and you need to look at surgery or some other option.

Stephen Ferber, MD: Exactly. And ultimately, I mean, it is a subjective thing, right? Because what we know is that even with an initial antidepressant, you have a little bit better than a one in three chance of achieving remission. That's not great to begin with, but are they going to be treatment-resistant right out of the gate? No. And so unfortunately, a lot of our definitions are based on our available treatments, where ideally we would be looking... I mean, when PCPs treat hypertension, they have to be getting better remission rates than we do. And so I think that if we had better treatments, the definition might change. But as it stands now, this is kind of the consensus.

Glen Stevens, DO, PhD: And I assume it goes without saying, but it's important to say that one cause of treatment resistance is the wrong diagnosis.

Stephen Ferber, MD: Well, so you bring up I think a really important issue, which just kind of reflects psychiatry as we are today. So when I'm training residents, what I typically tell them is psychiatry today is how rheumatology must have been in the 1940s, where lupus was still a thing in 1940. They just didn't know that it was an anti-double-stranded DNA antibody that caused it or what the optimal management strategy was. And that's where we are.

So if you go by the DSM, the Diagnostics and Statistics Manual, which has every diagnosable psychiatric condition, you can have over 200 unique combination of symptoms and still meet criteria for MDD, which is kind of mind-boggling when you think about it, that you could have 200 plus patients with completely different symptom profiles, all being diagnosed with MDD, and then saying, "We're going to manage them the same," because ultimately, there is no way that their distinct symptoms reflect identical underlying neurobiological abnormalities. And so unfortunately, psychiatry is a really nonspecific field now, and that's not where we need to be.

Glen Stevens, DO, PhD: I'm confident you're going to get there.

Stephen Ferber, MD: Well, I hope so. I hope when I retire, it's a different game. So fingers crossed.

Glen Stevens, DO, PhD: So the other sort of shadow here is pseudo-resistance.

Stephen Ferber, MD: Yeah.

Glen Stevens, DO, PhD: I'm sure compliance in psychiatry is a problem, and if someone's not really taking their medication, are they really resistant, or did they just not take the medication, or they have some GI issue, or absorption problem, or something else. So talk about pseudo-resistance.

Stephen Ferber, MD: Exactly. So I mean, if we think about it, so let's take a person who had their first major depressive episode and they were trialed on sertraline, fluoxetine and nortriptyline, and never even approached remission with either of those, so that's case one. Let's take case two of somebody who had their first major depressive episode. They were placed on sertraline, achieved remission for a decade, and then suddenly some life event happens, they get depressed again, and they are not able to achieve remission with any subsequent trial. And then, let's take another person, first major depressive episode, who is completely serotonergic intolerant, where they have sexual side effects, GI distress, all of those individuals would be classified as having TRD. Should we treat them the same? Absolutely not. We just don't know how we should be treating them. And so I think that you're completely correct that treatment-resistance is this blanket term that really doesn't offer a lot of details on how or why the person got there, and offers really no insight into what we should do differently.

Glen Stevens, DO, PhD: So if we look at five of the common psychiatric disorders, and of course, depression up at the top, but then generalized anxiety disorder, panic, obsessive compulsive and post-traumatic stress disorder, is resistance variable depending in these five different disorders?

Stephen Ferber, MD: It is.

Glen Stevens, DO, PhD: I assume some are more treatable than others?

Stephen Ferber, MD: It is, yeah. So I think that it reflects mainly whatever the response/remission rates are for whatever pharmacological intervention we're offering. So for example, I mean, well, really any psychiatric condition can be treatment-resistant. If you have a treatment-resistant phobia of dogs, I don't know how to help you, but I think that if there are... Certainly, the conditions you just listed, those are the bread and butter of what we do at the Psychiatric Treatment Resistance Program. But you're right that OCD typically tends to have a higher rate of treatment-resistance, simply because the mainstay of treatment is exposure, response prevention therapy, and then serotonergic agents. Once those are failed, a patient has failed those, you have the option of TMS or neurosurgery. And so I think it just really reflects the lack of detailed and overarching treatments that we have.

Glen Stevens, DO, PhD: So we'll just stick with depression. So you've had them on two adequate medications, know they're taking the medications, there's not a reason it's not getting into their system, and not improving their symptoms. Do you go to a third or where do we go? I guess you have a discussion with the patient, or is it time to do some type of intervention that's not medication based?

Stephen Ferber, MD: That's a great question. So what I would love to be able to do, and what we're unfortunately unable to do, is to be able to take a patient, look at their specific symptom profile, look at some neuroimaging finding on resting state or functional MRI, or a biomarker, and then say, "Based off of your specific cluster of symptoms, we know that you're going to have a higher chance of achieving remission with intervention X." We can't do that right now. And so it's extremely nonspecific.

And so again, I tend to have a bit of an anti-medication bias, simply because if you just look at the global remission rates, they're lower with pharmacological interventions than with any of the other options, mainly the interventional options. And so the reason why we don't offer these things to patients right out of the gate is mainly because of insurance. I mean, I think that if I had depression, would I want to take fluoxetine for the rest of my life or try a course of TMS? The answer is pretty easy from my perspective, but unfortunately, there's no way insurance would approve it until I've tried two, three, four medications.

Glen Stevens, DO, PhD: So tell us a little bit about TMS. How do you do it? How often do patients need to come? Effectiveness?

Stephen Ferber, MD: Sure. So generally, they're the big three when we talk about interventional options for treatment-resistant depression. So there's TMS, there's ECT, and there's ketamine. And so for TMS, which is transcranial magnetic stimulation, that is the delivery of a magnetic pulse to stimulate or inhibit populations of neurons in different brain regions, most commonly the dorsolateral prefrontal cortex. And so the thought is that one of the most consistent neuroimaging findings in depression is left dorsolateral prefrontal cortex, hypoactivity. And the thought is, regardless of why that's the case, if we are able to boost that population of neurons through long-term potentiation, we might be able to restore this dysfunctional connectivity or activity in that area. And so as it stands now, TMS is delivered usually five days a week for six weeks. And so it's an extremely labor-intensive process on the part of the patient.

Glen Stevens, DO, PhD: And are most people on a medication while they're doing the TMS?

Stephen Ferber, MD: Yes.

Glen Stevens, DO, PhD: I would assume.

Stephen Ferber, MD: We recommend that you stay on your antidepressant. Many patients ask, "Why would I do that if the antidepressant didn't work?" The thought is that TMS induces some degree of neuroplastic changes in the brain that allows the person to respond better to a medication from a relapse prevention perspective, even if that wasn't adequate in treating the acute symptoms. And so usually, in 99% of the cases, we advise patients, "Stay on your medication while you're getting this treatment."

Glen Stevens, DO, PhD: So sorry, go through the treatment paradigm, and I come see you, how long is the treatment? How many times do I need to see you? Is it uncomfortable?

Stephen Ferber, MD: So for TMS, most people will do five days a week for six weeks, a total of 30 treatments. And so generally, they're in the chair for anywhere from 2 to 14 minutes, depending on the protocol. So it's not a particularly lengthy treatment, and their job is to sit still while these magnetic pulses are delivered. The way it would feel to you, Glen, is really someone just tapping on your head. So it's not painful. Occasionally, because the area of the dorsolateral prefrontal cortex, that leads to some muscle contraction in the forehead, but again, it only happens during the actual treatment, and very, very rarely painful.

Glen Stevens, DO, PhD: Left or right-handed, does it matter, your dominant hemisphere, or no?

Stephen Ferber, MD: No, not for TMS. I mean, so generally, the most consistent neuroimaging findings are our left DLPFC hypoactivity and right hyperactivity. And so usually, all things being equal, the majority of the evidence corresponds to left-sided hypoactivity, and so that's where we start. There are certain situations and psychiatric comorbidities where we would potentially do a different protocol, but I would say 80% of the time, we're doing the same thing, regardless of those independent factors.

Glen Stevens, DO, PhD: So you treat me if I'm going to have a positive response time period?

Stephen Ferber, MD: Generally, people will begin to notice benefit within the first two to four weeks. And so it does not work immediately. Our job during those first two weeks is reassure, reassure, reassure. The fact that they're not feeling any better has no predictor on whether they ultimately will achieve remission. And then, if someone is actively responding but not achieved remission, what we will do is petition their insurance company to extend the acute course. For whatever reason, in Ohio, that's been next to impossible to do. In other states, it's a little bit better.

Glen Stevens, DO, PhD: So you treat me, I feel much better, I'm doing fine. Three years later, relapse. I guess medication again to see what happens, or do you go right to TMS again?

Stephen Ferber, MD: Yeah, well, that's a great question as well. So generally, what the studies show, and this is one of the benefits of TMS relative to other treatments, is that it's an extremely durable treatment, meaning that those who achieve a response or remission are likely to stay that way. So between 68 and 72% of individuals who achieve either response or remission respectively will remain that way for the subsequent 24 months after their acute course of TMS. Now, we don't have studies that look longer than that, but it theoretically could be longer. If you were to relapse in the future, whether that's 1 year, 2 years, or 10 years down the road, we do the course again. And luckily, there is a very, very high likelihood that if you respond once, you will always respond.

Glen Stevens, DO, PhD: So somebody has epilepsy, they're on a seizure medication, it's controlling it, but then it's not, they have a surgery, seizures stop, they're on medication. Then, at some point, the epileptologist will wean off the anti-seizure medication.

Stephen Ferber, MD: Mm-hmm.

Glen Stevens, DO, PhD: Do you guys do that? So you give me TMS, I'm out a year, I'm doing great, I'm taking my triptan. Do I need to take it? Is it leave well enough alone? I'm always a big fan of leave well enough alone.

Stephen Ferber, MD: Yeah.

Glen Stevens, DO, PhD: But what do you guys do?

Stephen Ferber, MD: So Glen, it's a numbers game. So generally speaking, if somebody has one major depressive episode, they have around a 70% lifetime risk of having a second. If they have two, that goes up to 90%. If they have three, that goes up to around 99%. And so ultimately, it's the patient's decision. We almost always advise, "Stay on your medication," because the first goal, whenever we see somebody who's in an active episode is, "Let's get you better." And the second goal becomes, "Let's keep you better for as long as possible." There's no cure for depression. And so ultimately, the relapse risk will always be non-zero. Our job is to get that number as low as possible.

Glen Stevens, DO, PhD: Anything claustrophobic about the TMS or-

Stephen Ferber, MD: No.

Glen Stevens, DO, PhD: ... no, because it's above?

Stephen Ferber, MD: Yep, it's kind of this big metal plate that rests on your head. So as long as you can sit still for 2 to 14 minutes, it would not any difficulty for you.

Glen Stevens, DO, PhD: What age can you treat to, how young?

Stephen Ferber, MD: That's a good question. I mean, well, it's FDA approved for 18 and above, I believe. But theoretically, I mean, we typically don't encounter that, just because if you're younger than that, you haven't had enough time to achieve treatment-resistance. But theoretically, it could be used in any age population. But again, we're not seeing 12-year-olds with TRD. So, but I think again, if we did have a pediatric patient, my guess is insurance would say, "No way."

Glen Stevens, DO, PhD: ECT.

Stephen Ferber, MD: Yes.

Glen Stevens, DO, PhD: Discuss it with depression that's resistant.

Stephen Ferber, MD: Yeah, so with all of these options, what I always tell patients is, "Listen, if there was an option that was the most effective, had the fewest side effects, and was the easiest to do logistically, I'd tell you, and I'd recommend that. Each of these treatments have their pros and their cons." And so with TMS, the pro is extremely well tolerated, extremely durable. The con is a slightly lower chance of achieving remission, and then it takes a while to work. ECT is the gold standard, and I wish that there was a different gold standard, because there obviously is a fairly significant side effect burden with ECT.

But if a patient comes to me and says, "Dr. Ferber, what is the single intervention that gives me the highest chance of having no remaining symptoms of depression?" the answer is ECT. And I think that there's obviously been a huge stigma. It's portrayed in the media in probably one of the worst ways possible, where it makes it look like torture. But this is something that is a necessary tool for psychiatrists right now, especially for individuals who just don't respond to these other options.

Glen Stevens, DO, PhD: Well, you know, I'll just share with you that in the '70s, I worked at a psychiatric hospital in Canada, and it was a criminally insane ward. So everybody had had a psychiatric disease, but had broken the law. And that was my first experience with ECT. Now, this was in the '70s, 50 years ago.

Stephen Ferber, MD: Yeah.

Glen Stevens, DO, PhD: So I'm sure 50 years ago, how it was done is different than how it's done now.

Stephen Ferber, MD: Were they doing unmodified or did they receive general anesthesia?

Glen Stevens, DO, PhD: No, general anesthesia.

Stephen Ferber, MD: And so that's the biggest difference, is every single depiction of ECT in the media, whether it's One Flew Over the Cuckoo's Nest or Requiem for a Dream-

Glen Stevens, DO, PhD: Yeah, that was the same time, right?

Stephen Ferber, MD: Yeah, so the patient is not receiving general anesthesia, and so that's what we call unmodified ECT. That's still done in third-world countries. But what I tell patients usually who are understandably apprehensive about this is, "Imagine getting your appendix taken out in 1924 versus 2024. Appendix has gone both times, two very different experiences in terms of surgical technique, risk of infection, pain control. ECT is no different." It's the same name, but it has undergone significant technological advancement, where it would be unrecognizable to a psychiatrist performing ECT in the '60s or '70s.

Glen Stevens, DO, PhD: And then, you mentioned ketamine. Is it ketamine, or esketamine, or...

Stephen Ferber, MD: It's both. So ketamine, the racemic version, that's what we use for the intravenous infusion, which can be done for both chronic pain and depression. Esketamine, or Spravato, is the FDA-approved nasal spray.

Glen Stevens, DO, PhD: Okay, and its use in depression?

Stephen Ferber, MD: So ketamine stands tall in terms of its rapidity of response. So generally, once we find the dose that works for somebody, within 24 hours, they will feel the benefits. Nothing comes close to that in psychiatry. And so for individuals such as myself who are extremely impatient, ketamine is a great option, and that if you pursue that, you will get better more quickly. The issue is mainly lack of long-term data.

So Spravato was FDA approved in 2019, IV ketamine is not FDA approved. We don't know what happens if you receive repeated administrations for a decade, two decades, because that data, it just doesn't exist yet. And so I think that there's a bit of a question mark, but this has been a great supplement for people who do not want to do ECT, because at least in many of the studies, the response remission rates are not dramatically different. And so this potentially is kind of the 1B to ECT's 1A.

Glen Stevens, DO, PhD: So refractory depression, chances are you're getting one of these three modalities. Is there a fourth one, a fifth one?

Stephen Ferber, MD: Yeah. So I’m early in my career, I have not had a patient who I have not been able to get to remission with one of these three. My boss, Brian Barnett, who is the co-director of our program, he has been in that situation. And then the options are neurosurgical, mainly VNS, a vagus nerve stimulator. And so that would be the next step if one of these three didn't work. There also are more advanced medication strategies, which can be used. Monoamine oxidase inhibitors, which you may be familiar with, those are typically prescribed in the case of other medication failures. But outside of those options, the other ones are all investigational.

Glen Stevens, DO, PhD: Deep brain stimulation being used at all, or not so much?

Stephen Ferber, MD: So there was a large study called the BROADEN trial, Helen Mayberg's Group at Mount Sinai was one of the main kind of sites for this, which looked at DBS and the subgenual cingulate for treatment-resistant depression. The initial study was negative, but that may have been because they did not have a long enough observation period after implantation, where we know the DBS and other conditions can take sometimes six plus months to demonstrate effectiveness. And so there's actually a group that is looking to try this again, and Cleveland Clinic, knock on wood, may be a site for that. And so I think that that's a to be determined.

Glen Stevens, DO, PhD: So outside of depression, uses for TMS and other disorders, schizophrenia, OCD, anxiety, useful, not useful?

Stephen Ferber, MD: OCD, yes. So we have different protocols targeting either the pre-SMA or the dorsomedial prefrontal cortex for OCD. Additionally, for generalized anxiety disorder, there are protocols. And I think that, again, so this is my personal bias, TMS I think is hopefully going to be the future of psychiatry, because ultimately, what we know is that if we go way back into the origins of psychiatry, where the mind and the brain were thought of as distinct entities, we know that's wrong. We also know more recently that depression is not due to low levels of serotonin.

Ultimately, most likely, every single psychiatric condition is a disorder of neural circuitry, dysfunctional neural circuitry, where there are different regions of the brain that are not communicating effectively, whether it's hyperactivity, hypoactivity, asynchronous communication. And so once we can identify the dysfunctional neural circuits for our disorders and target them, then we can really kind of have a more specific symptom-based approach to treatment. Because right now, when you give somebody fluoxetine, it increases serotonin in every area of the brain where there's a serotonin receptor. And ultimately, I mean, it can get the job done, but it's so imprecise. And so I think that one of my old supervisors in residency, he used to say that psychiatry should be a fellowship after neurology. And at the time, I didn't know exactly what he meant, but I think what he meant now is it's a lot easier to explain why somebody has hemiparesis after an MCA stroke and why somebody has a flashback in PTSD. It's the same organ of dysfunction, right?

Glen Stevens, DO, PhD: If we move to some of the other disorders, we look at obsessive-compulsive disorder, I do a fair amount of Gamma Knife, and I know there's some literature of doing capsulotomies and-

Stephen Ferber, MD: Yep, absolutely.

Glen Stevens, DO, PhD: ... those types of things for OCD. How does that work?

Stephen Ferber, MD: So it is so hard to get patients in. I mean, so I think OCD, the truly treatment-resistant OCD patients are some of the sickest individuals in psychiatry that I've seen. And generally speaking, we're doing TMS first and then we're referring to you guys for capsulotomies or cingulotomies. And I think that that's something that, again, there's this huge barrier where patients don't like the idea of a neurosurgical approach to a psychiatric condition, but would have no qualms about it if they had a brain tumor. And I think that that's where we have to get better in terms of explaining this in a way of, "Hey, listen, the pathology are in these areas," describe it in a way that's accessible to patients, so that we can get more in the door, because I think that it's dramatically underused.

Glen Stevens, DO, PhD: So do you consider yourself an interventional psychiatrist?

Stephen Ferber, MD: I do. So it's a new term, a new subspecialty. Most physicians, when I say that, they have no idea what I'm talking about. And so this is the procedures within psychiatry, and I think that my entire job reflects just that, seeing consultations and then performing it. But just interventional cardiologist doing caths all day, that's what I'm doing.

Glen Stevens, DO, PhD: Yeah, I think it's a natural progression, right?

Stephen Ferber, MD: Yeah.

Glen Stevens, DO, PhD: And I think that it's great to see sort of this new field evolving, because otherwise you have all this treatment paradigm that you're not utilizing, or you're asking somebody else to do it. You know they're not really vested in it, they're just the technician.

Stephen Ferber, MD: Well, I mean, exactly. And I think that the way that it's done in most facilities is if a hospital wants to develop an ECT service, they'll tell the inpatient doctors, "Hey, we're going to need you to do ECT." And you go take a five day CME course, and then you're the ECT doctor there. And I think ultimately, there's a better way to do it, to really have a core group of interventional physicians, where this is their bread and butter. And I think that's one of the benefits of our program here, the Psychiatric Treatment Resistance Program, is that we are kind of a fully-integrated interventional service, which doesn't exist in that many places in the country.

And so what we have that other programs, which may be more siloed, don't, is the opportunity to offer the patient all of these modalities from the initial consultation, where if you go to a different institution, you may be referred for an ECT consultation, and if you have a medical contraindication and can't do it, you start the process over again at the ketamine service. And so here, we're fully integrated. All of our doctors can perform all of these. And so I hope and think that this is the future.

Glen Stevens, DO, PhD: So treatment-related schizophrenia does have a medication that can sort of effectively work like the interventions that you're using, clozapine.

Stephen Ferber, MD: Not a fun medication to be on.

Glen Stevens, DO, PhD: Do you use it?

Stephen Ferber, MD: Yeah, I mean, we use it because we have to. I mean, it is not a fun medication to be on in terms of the sialorrhea, the weight gain, the constipation, and then the potentially very dangerous side effects of myocarditis or a granulocytosis. Again, I want a future for psychiatry where much of what we're using today is completely obsolete, because we have options that are more effective with fewer side effects. With clozapine, though, we kind of have to, and if someone has failed antipsychotics, then this is the option, or ECT. I will argue that I think ECT is dramatically underused in the psychotic population, but extremely effective, and actually one of the few evidence-based interventions for clozapine-resistant schizophrenia.

Glen Stevens, DO, PhD: Okay, what's on the horizon?

Stephen Ferber, MD: So a lot. Psychiatry I think is the most rapidly-evolving field in medicine, simply because we have the furthest to go, but there are a lot of exciting things. And so a couple of them would be the psychedelics. So I think that these medications-

Glen Stevens, DO, PhD: Psilocybin.

Stephen Ferber, MD: Yep, psilocybin, LSD, MDMA, these probably will be FDA approved within the next five years, and they've been shown, at least with initial studies, to work on different neural circuits than what we have, so mainly the default mode network. I think the biggest advancement in psychiatry is really going to come from what are called biotypes, basically defining clinical subtypes of depression. Because ultimately, with major depressive disorder, again, you can have 200 plus unique combination of symptoms. And that heterogeneity really impedes our ability to provide specific, tailored treatment.

And so a lot of groups are looking at if there's any way that we can predict remission rates with any kind of test. And so there's one group that we've actually partnered with in Silicon Valley that has an EEG algorithm to predict ECT and TMS response rate, so that ideally, a patient gets a six-minute EEG. I mean, very, very minimal work on the patient's part. Before they even come to see us, the psychiatrist gets a printout saying, "73% likelihood of response to TMS, 37 for ECT." That would be a game changer. And so I think that the real area of opportunity in psychiatry is for groups such as them to figure out how do we have any kind of more specific ability to diagnose these conditions and to separate them into meaningful and clinically relevant subtypes?

Glen Stevens, DO, PhD: Well, you've done the best thing you can do in that, is you've offered hope.

Stephen Ferber, MD: Yes, yes.

Glen Stevens, DO, PhD: I like what I'm hearing today, that-

Stephen Ferber, MD: Absolutely.

Glen Stevens, DO, PhD: I like the fact that the field is evolving and changing. I'm an interventionalist type person myself, so I like that. It's exciting-

Stephen Ferber, MD: It’s exciting.

Glen Stevens, DO, PhD: ... that the field is changing that way. So we appreciate your taking the time to walk through this with us-

Stephen Ferber, MD: Of course.

Glen Stevens, DO, PhD: ... and tell us what's exciting going on. Look forward to having you back, and you can share your continued experience with us.

Stephen Ferber, MD: Wonderful. Thank you so much for having me, Glen. Appreciate it.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's @CleClinicMD, all one word. And thank you for listening.