How to heal the pathology of brain circuitry with a wearable, take-home device to treat depression

PROVIDENCE, R.I. – The campus of Butler Hospital is awash in fall colors as the sun moves toward the horizon, on Thursday afternoon, Nov. 7.  The shift of nurses, doctors and patients is on the move, the daily changing of the caretakers, as ConvergenceRI struggled on trekking poles to reach the main entrance, on time for an interview with Dr. Linda Carpenter, M.D. One of the pioneering neuroscience researchers at Butler Hospital,  Dr. Carpenter is the lead clinical trial researcher on a new, take-home device (Relivion) created by Neurolief to treat major depressive disorder, a chronic and recurring condition that afflicts millions. The interview took place in Dr. Carpenter’s office at Butler Hospital, a portal into a space defined by stylish design and acute attention to detail. Dr. Carpenter is wearing a turquoise scarf that depicts the brain’s synapse structure, replete with dendrites and axons depicted in black. Two days before the interview, former President Donald Trump had been elected the 47th President of the United States, as if the entire nation had been victimized by a mass psychosis where facts no longer seemed to matter. That evening, members of the Rhode Island Senate would convene in a caucus that replicated a medical intervention, as Senators endorsed the continued leadership of Senate President Dominick Ruggerio, despite indications that his chronic health conditions had taken a severe toll. Earlier this summer, ConvergenceRI had conducted an interview with Dr. Carpenter, “Listening to what your brain is telling you,” following her being awarded the Clinical Transcranial Magnetic Stimulation Society Gold Medal. Dr. Carpenter serves as director of the Transcranial Magnetic Stimulation Clinic and Neuromodulation Research Facility at Butler Hospital, a division of Care New England. ConvergenceRI: I am amazed at the latest work, which seems to be just remarkable, in terms of its groundbreaking nature of treatment: The idea that people can have a take-home device that can help them with their treatment of drug-resistant depression. The treatment moves forward in such a way that it may help patients to overcome everything from long-term depression to migraines.     CARPENTER: Right. The particular device that we are talking about today which is the subject of clinical trial that we just finished, is the same device that they have already gotten approved for migraines, but the stimulation pattern that it gives for depression is different. You would use this device [taking off her glasses to put on the device to model it], they may look the same, but the stimulation of the prescription, if you will, would be different for migraine than it is for depression. But, it is incredibly exciting, because we don’t yet have any FDA-approved home-use devices for depression. ConvergenceRI: My first question to you is, “How would I be able to get one of these devices?” How would I qualify? Are the clinical trials’ hurdle now over?    CARPENTER: The clinical trial was conducted at multiple sites around the country, and I think we also had an Israeli site [the Relivion corporate headquarters are based in Israel with a facility in Florida]. The clinical trial proved the efficacy [of the device] by randomizing people in active or sham, right? The data demonstrated a superior outcome for the people who had active [devices]. At this point, the whole package of results has gone to the FDA, maybe about a month ago. And, they are processing it. Before the FDA started this trial, they gave this company what is known as a “breakthrough designation,” to help them get onto a fast track for going through the regulatory process, because they identified a need for patients with treatment-resistant depression to have [access to a device] at home. Many of [the patients] can’t come to our clinic five days a week for TMS [transcranial modulation stimulation], or they can’t come in for ECT [electro-convulsive therapy]; you would have to have someone drive [the patient] here and then drive them home. The FDA identified the need and put [the firm] on fast track. The company expects, and I don’t work for the company, but I think they expect to receive FDA approval in early 2025. And then, when that happens, they can commercially market the device. Now, how will that work? I don’t know. This is the first of its type, There are a couple different of ways that this can go. It could be that you come to your doctor’s office, they supervise you using it a couple of times until they are confident that you can use it properly. And then you take home the device, use it, come back, check in every two or three or four weeks, something like that. There is also this question of durable medical equipment, which is out of my wheelhouse and how it would work. Which is where you are a clinic and you actually sell the device to the patient. You have a stock of them. I don’t know what the business model will look like. What I do know is that it’s a prescription device. So, you will have to be monitored by a doctor. It doesn’t mean that it has to be a psychiatrist. You could go to a primary care doctor. But, when it first rolls out, because it is FDA-approved for people who have not gotten better with at least one anti-depressant medication, it will b prescribed typically by a psychiatrist at first, I think. And as broadly as it can be disseminated, that would be great. Because the goal would be to reach all of those patients who can’t come to a specialty clinic. And there are a lot of those. If you think about, when we talk about treatment resistant depression, basically about a third of patients don’t get better with standard anti-depressant treatment. And, that’ a huge number; it’s millions of patients, [looking it up on her computer]. There are some 21 million patients with depression, 9 million being treated with anti-depressants, and 3 million meet this criteria for treatment resistant depression if they don’t get better with a standard anti-depressant. We are looking to find and implement a treatment that would be more convenient and accessible – and I am very excited about that. ConvergenceRI: For me as the journalist, the question is: How could I get one of these devices and write about it, and perhaps become part of the follow-up. The goal would be, that as much as a scientific endeavor, I think that for people to understand what is going on, it might be helpful to have a journalist who can write about the experience and share that…     CARPENTER: …It would be fantastic. ConvergenceRI: …in a comprehensive fashion, I am willing to raise my hand…     CARPENTER: …And volunteer? ConvergenceRI: I would volunteer to become a patient, or whatever is required, to do this, because I think for all the studies you can do, having someone to actually talk about it in a cogent fashion is intriguing to me.     CARPENTER: Yes. You can go onto the company’s website and get a prescription for the migraine device. And, I don’t how you do that, I just noticed this (Relivion website for migraine) today, and I think you can purchase it and have it sent to you, and it would be very similar. You would get the experience of what it is like; they have a prescription and then there are accessories. ConvergenceRI: Would that come from through my primary care physician?     CARPENTER: I was just looking to see if you could get a prescription under the migraine indication. The trial would go on for 60 days. This is a brand new website, (there is a listing, “Getting started. Telehealth and find a doctor.”) You might b able to interact with this website and get one for a migraine, with a telehealth physician. It looks like they give you ways to do that. ConvergnceRI: I will consider following up with that. From what you have described, it seems like it is a major breakthrough in treatment, with the possibility that this device will be something that will change the way that depression is treated. And perhaps conditions that are linked to depression, such as obsessive compulsive behavior.     CARPENTER: Well, we haven’t tested those other indications. But I think you have the right idea. And, in fact, here are a number of devices, if you just Google them,  you can find them. But the difference between this and those [other devices] is that they haven’t been put through large, randomized control trials, which takes a lot of time and a lot of money. ConvergenceRI: Have you gone through Phase I, Phase II, and Phase III clinical trials?     CARPENTER: The clinical trials design are not the same for drugs as they are for devices. This would be a device that they tested it in an early pilot study. And, they have done all their safety testing before they came to this clinical trial. And, then, I guess, after FDA approval, this is all that will likely be needed according to the FDA to get the clearance. And then, after the clearance, there will be a lot of questions we need to address. We studied this, with people using it every day, active or sham, for a period of eight weeks. And then, what happened in this clinical trial, at the end of eight weeks, you got to crossover and go to active, if you had gotten the sham, and if you had already got active for eight weeks, you could, continue with eight more weeks of active. There were a number of questions built into [the study]. One, if you aren’t all the way better by eight weeks, and you keep going, will you get more people into remission? And, the answer to that question was yes, because more people kept getting better. And the other question was: If you had sham for the first eight weeks, and now you get the real device, can you replicate that the same percent of people were getting better, and we did. But some of the questions we haven’t answered are: OK, we’ve had people using the device for up to 16 weeks, what does the maintenance look like? Do you stop using it? Do you continue to use it? Do you continue to use it less often? How long will it last? Is it something that you are going to pick up when you start to slip and your [depressive] symptoms start to come up again? As soon as the FDA approval happens, then those will be next types of studies that we are doing. And also, we will be doing more mechanism of action studies. To do scans, before and after treatment, to look at how is it changing connections in the brain, and the way it does. ConvergenceRI: How has it changed your life? You have spent a large amount of time working on this, to see it come to creation. To now have a device that is sitting on front of you on your desk, and it seems to work, what is that like for you as a researcher, as a neuroscientist?     CARPENTER: It is really exciting. I am very big on “the bench to bedside.” Getting all the way to implementation is something that I really, really enjoy. You know, a few of the hurdles that lay ahead are that this is a small, start-up company that is looking for a big company such as Pfizer to buy them and co-license it to help facilitate the next bunch of clinical trials that need to happen to answer all these additional questions. A lot of this is now in the hands of the device manufacturer, to take the next big steps to help get the device out there. I’m thrilled to be able to talk about it. I am thrilled to know that it works and to recommend it. But, access is so important. And, like all these other new treatments, if people can’t afford them, if health insurance doesn’t cover it… There needs to be access. I am just really hopeful that the pieces fall into place and that they are taken care of, because that is not [the focus of] my work. My work is the scientific work. To get it to implementation, so I can see patients using it. And not just in my clinical trials. We want people to be able to be use it; I think that will take some time. To answer your question directly, there is a little bit of antsy-ness about wanting to keep moving forward, and doing the next thing, to get their money and to get their companies and their commercial model all built. But, it’s exciting. It’s exciting to have been a part of designing the trial to help pick the sites, and make sure that it was conducted with scientific rigor. And to have good data. Because, you know, there are a number of devices out there. Congess passed a law in 1972 that said the FDA will regulate medical devices. And, ever since then, all the biomedical devices go through FDA. But, there were a bunch of devices on the market before 1972. And they were grandfathered in. They have been able to market themselves legally, without ever doing clinical trials, So there are all these devices that patients can get that they advertise for depression or for anxiety or pain, or to improve your dreaming, or something. But they just don’t have the science behind them. Psychiatrists and other physicians tend not to prescribe them; patients sometimes find them and ask, “Will you sign this form I got online?” But they haven’t really been incorporated into the mainstream of treatment because they haven’t had the science. So now, we have the first one with the science. And that is really exciting. I would like to see it become used as a regular treatment for depression. ConvergenceRI: What does it feel like for you to be able to help direct the first of its kind device with the promise of something to be so helpful to people, who are often struggling to get by day-today?     CARPENTER: It feels great. It feels really great. We all want to do something, you work with patients, and you are experiencing their suffering, and the disabling nature of the depression. And, the problems with side effects. And, the burdens on families and the economy. It feels great to have something. It will feel greater when I can go, here you are. There are so many people who were involved with the device. I didn’t design it; I didn’t invent it. And, the company did really elegant work in putting it together. It has a really elegant interaction with your smart phone that walks you through how to use it, that checks to make sure that the device is on right, and that sends the information to the cloud that I can look at on a dashboard to see if the patient is using the device safely. But, you know, we are not completely at the finish line until it is disseminated. ConvergenceRI: Let me go back and ask about what is actually happening in the brain with the device. And please correct me if I get this wrong. The idea is what you are working with is the way that the brain can reconfigure the way that the synapses and the neurons fire, essentially that there is a learned pattern that takes place, so if you fire the sequence enough times, it becomes the learned pattern in the brain, and it doesn’t go back to all of the intermediate steps. It goes from A to F, without having gone through B, C, D, and E to get to  F. What the device seems to  be doing is retraining, if that is the right “verb” to use, to get the neurons to fire differently.   CARPENTER: Right. ConvergenceRI: To take the “memories” that are contained, if “memory” is the right word, of what gets lost in the translation of the firing of the synapse. Is that accurate?     CARPENTER: That’s a good way to think about it. Think about it like a computer. The computer has all these different parts that have to interact and, if one part breaks down, then the other parts might go around that part. This part might have the control of that part, like a circuit board. Think of depression like a circuit board. And just like you said, A, B, C, and D. And the circuits are connected by synapses, neurons and synapses, right? And so, like you said, if the part of the reward center and joy is turned off and not coming on, and the fear center and anxiety is on when it shouldn’t be, and the top control isn’t telling the others this isn’t the time to be anxious. This isn’t the time to be turned off, this isn’t the time to be attending – all those different signals. So, we know that there are these functional changes in the brain when someone is depressed. And, by and large, you can see when people get better, although depression has a lot of different versions, right? There are a lot of different versions of depression. If you look at all the different symptoms, and there are lot of different ways that it can look. But, in general, if you think about circuit pathology, that the circuit Is not working properly… ConvergenceRI: Circuit pathology?     CARPENTER: Yes. Again, if I have a lot of anxiety in my depression, then my amygdala, its connections to other things are not being regulated. We want our brain to say, “Oh yes, be fearful,” when it is appropriate to be fearful, when you are in a terribly dangerous situation. But not when you are trying to relax, and your reward center should be able to turn on when you experience certain things. And so, negative old memories should stay put, and not come in and re-evaluate what is happening in the present, The question of how the device’s treatment for depression works to fix that is unanswerable. How does psychotherapy fix that? How does ECT fix that? How does medication fix that? What we know is where the device has its actions. Or where EMS has its actions. Or what Prozac sticks to on the molecule, right? And what we know about this device is that it stimulates some peripheral nerves, branches of nerves called the trigeminal nerve in the front and branches of these nerves in the back, and these are right underneath your skin, these nerves are stimulated in this synchronous way, carrying messages down to the brain stem. And, this goes up through a bunch of connections, the solitary tech nucleus, the hypothalamus, and gets into the nodes, as you will, of the circuit. How that fixes the regulation is the question. ConvergenceRI: Am I asking the right questions?     CARPENTER: Oh, yes, I think they are great questions. ConvergenceRI: Thanks. Trying to translate what you are saying into language that people can understand, that’s part of the problem. I think I get some of it. But I am very much in awe of what it takes to translate what is happening, and the way that you then see it. There is clearly a difference between causation and correlation.     CARPENTER: Just think about Prozac’s impact on the serotonin uptake inhibitors And people said: It sticks on this little thing on the cell and it causes more serotonin to be in the cell. It’s not like we’re all down a quart of serotonin; it still is changing the circuits and how they talk to each other. And sometimes, we act like we know exactly how a treatment works. How does psychotherapy work? And that is really a retraining right? Forcefully creating new habits. ConvergenceRI: How tied into other senses is this work? With psychotherapy, you have to listen. In terms of drug intake, it is all about modulating how we respond to pleasure, versus things that are not pleasurable, and the wirings that enable that to happen.     CARPENTER: That’s the black box, the wiring that enables it to happen. So, that when a pleasant thing happens, joy, dopamine, the reward circuit is firing. You see your grandchild, you see your friend. You have a good thing happen. The common bottom line seems to be getting all those different functional areas of the brain to coordinate properly, particularly with top-down control, turning off things that are not appropriate and allowing things that are. When reward circuits are down, people feel apathetic, they feel no interest in things, no drive to pursue things. The last step is making the symptoms go away. Each of the treatments we talked about has a different way of approaching it.