Agita, which first appeared in American English in the mid-late 20th century, comes from a dialectical pronunciation of the Italian word acido, meaning "heartburn" or "acid," from Latin acidus. (Agita is also occasionally used in English with the meaning "heartburn.") For a while the word's usage was limited to New York City and surrounding regions, but the word became more widespread in the mid-1990s.

It's at this point that I remember-1the mid 1990s were, now, a long time ago.

This specific agita that I'm referencing? It's about bipolar depression. Regular readers will be familiar with the fact that the editor and most frequent author here on The Frontier Psychiatrists newsletter, Owen Muir, M.D., has bipolar disorder. For most people with bipolar disorder, most of the time spent sick? It is time spent depressed.

There is a paucity of options with strong evidence for bipolar depression. The most famous medicine for bipolar disorder, lithium (link to Dr. Chris Aiken’s awesome guide), which I still recommend people try as early in the disorder as possible, doesn't treat acute bipolar depression.

The only medicines with FDA labels for the treatment of acute bipolar depression are:

• Quetiapine (Seroquel / Seroquel XR) — bipolar I and II depression, monotherapy

• Lurasidone (Latuda) — bipolar I depression, monotherapy and adjunct to lithium or valproate

• Cariprazine (Vraylar) — bipolar I depression, monotherapy

• Lumateperone (Caplyta) — bipolar I and II depression, monotherapy and adjunct to lithium or valproate

• Olanzapine–fluoxetine combination (Symbyax) — bipolar I depression

And electroconvulsive therapy’s class II clearance includes acute bipolar depression in the language. Prevention of depressive relapse adds lamotrigine as one more option.

I'm gonna speed run the problem with the above acute drugs: they're all atypical antipsychotics, and that means weight gain, that means akathisia, that means Tardive Dyskinesia. They also just don't work for everybody. As someone has personally put up with every one of those side effects, I can tell you, with all the honesty that anyone could muster, the side effects are miserable.

We can go back-and-forth on the number needed-to-harm and relative risk of those medication's if we really wanted to, but I don't want to. I want to talk about something new that doesn't have any of those risks.

But before I talk about that new thing, I wanna point out that there's a problem. You see how short that list is? Do you see how limited the range of options are? That's actually because of an economic problem. There's a biological problem alongside it, but primarily we are talking about a problem with the market size of bipolar depression.

There are fewer people with bipolar depression than there are with unipolar depression.

That means if you're walking into the door of an investor for your New Thing. And it might help some kind of depression. You're not sure if it's gonna help bipolar depression, or unipolar, depression, or even work equally well in both? You're going to say it works for major depressive disorder a.k.a. unipolar depression, instead of bipolar depression. Because that increases the chance that you'll get the money to go develop The New Thing in the first place.

Here is a quick Claude-assisted graphic of the problem:

And that $1.7b number? It is an estimate based on all bipolar medicines (including maintenance and mania indications) not just a bipolar depression indication. The ration of the market size is 5:1, and so it’s slightly daft to go try to raise money for a smaller problem which also has the risk of bipolar therapeutic development.

We talk routinely about the unmet need of patients with depression. But not every FDA-labeled treatment for major depressive disorder causes obesity, movement disorders, and more. Bipolar patient's face even more pressure, and understandably, so, to continue taking medication, because the cost of relapse can be a life ruined.

If you don't believe me, just ask Kanye.1

Bipolar depression is more of an unmeetable need, at least in Pharma and med device—because between two pitches, the founder who promises to go after a market 5x bigger wins, all things being equal.

There's another problem—bipolar depression trials are less likely to show a difference between active agent and placebo. About half of clinical trial programs for unipolar depression drugs submitted to FDA fail. In Bipolar depression, the drug-placebo gap is smaller (roughly 55% vs 39% response)2. High Placebo response regularly erases it this difference—remember, the natural history of bipolar depression is to get better pretty quickly, and most drugs work relatively slowly, and so the natural history of the illness, including spontaneous remission, is often working more quickly than any drug could hope to work.

Return returning to my earlier point about raising money to solve the problem? Ardent founders would have to pitch “smaller market, and…wait for it…higher risk!”

That's bad math for fundraising, and so we see, essentially, a raft of me-too drugs to address this crucial problem. These options are not enough. I've previously written about the promise of accelerated transcranial magnetic stimulation, particularly the SNT approach, in bipolar depression. It does look like that's likely to work—but somebody has to do a large enough trial, submitted to the FDA, to change the label, and that just starts the conversation with payers about coverage.

Today we have more data, that's hopeful, but unlikely to lead to meaningful coverage, because the academic researchers chose to study something. I bring you: IV ketamine. For bipolar depression.

The authors of the KET-BD study included the following participants:

The Ket-BD study (Ketamine for Treatment-Resistant Bipolar Disorder) was an investigator-led, double-blind, midazolam-controlled randomized clinical trial conducted at 3 sites in Ontario, Canada, from July 2022 to November 2025. Participants included adult outpatients (aged 21-65 years) with a primary bipolar I or II disorder DSM-5 diagnosis with a current moderate to severe major depressive episode ([MADRS] score ≥21), having had at least 2 failed trials of evidence-based pharmacotherapies.

The subject were randomized to:

four 40-minute infusions of 0.5 to 0.75 mg/kg of ketamine or 0.02 to 0.03 mg/kg of midazolam, adjunctive to a stable dose of at least one antipsychotic or mood stabilizer, over 2 weeks.

There were more dropouts in the placebo group:

Of the participants, five — one of whom was assigned to ketamine — withdrew before the study’s primary endpoint.

Which to me speaks to the lack of integrity of IV midazolam as a blind, but the data on dose #1 didn’t support unblinding at that time point:

47% of participants correctly guessed the treatment allocation after the first ketamine infusion “despite the ketamine arm having greater dissociation during infusions.”

And the treatment worked:

The researchers reported that the mean MADRS score at 14 days was significantly lower in the ketamine group vs. the midazolam group (between-group difference = –7.3 points; 95% CI, –12 to 2.5).

The split between bipolar I and bipolar II (my usual “did the Study just enroll people with depression who wanted to get ketamine by pretending to have bipolar mania disorder in the distant past?” BS filter) was not completely unreasonable. It looks like they enrolled sick people.

My colleague Nico Grundman, at Ember Health, assures me that this is a routine part of their care, and that it works well. Here's another piece of data suggesting that that's the case. There's no FDA labeled treatment for acute relief of bipolar depression. There needs to be.

Dear Pharma companies, let's do this. Patients with bipolar disorder, like myself, need access to more treatments. Ideally those treatments will work quickly.

I feel pretty terrible that even as a Psychiatrist— and as clinical trial principal investigator— I have done precious little, personally, to advance the well-being of people who have the bipolar disorder that I am also living my way through. I feel guilty that I'm lucky enough to be able to get off-label treatments like transcranial magnetic stimulation and ketamine because, even though I'm not wealthy, I was able to scrape together the money. Most people aren't that kind of lucky. Most people don't even know if it would be worth their hard earned dollars or those of their family. I'm luckier than most. I haven't done enough, personally, to make it better for people like me. If this article reaches one person who gets to make the decision on which company to cut a check into next, and it's one that wants to make a big dent in bipolar disorder, feel free to call me, and I'll tell you it's a good idea. This will be less true financially than it will be emotionally, but I'm OK with that. Investing in the lives of people with bipolar disorder is the right choice.

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A brief note, to my readers, I keep most of these free. I don't get upset if you want to subscribe though. It helps support the mission. It proves to people who invest substantial amounts of money in this field of a human endeavor that my ideas have traction. Please consider subscribing.

I got to spend time on the DTRA podcast talking about what China is about. I hope you enjoy it.

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New Orleans
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Time: 5-9pm

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Sponsors include:

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I hope you enjoy getting to know someone I think of with the utmost respect and admiration, my coworker, Nogga.

I’ve been on the channel twice before: Once with carlene, and once solo, which are linked for ease of viewing.

Now…

The Nogga “BTS” Interview

Owen: Would you like to introduce yourself for our readers?

Nogga: I’m Nogga Schwartz. Owen’s “assistant” and colleague for some time now.

Owen: We went to Los Angeles recently to film two videos, it turns out, for the Soft White Underbelly channel. Can you tell the backstory of me approaching you about doing this in the first place?

Nogga: I heard Owen was going to be on Soft White Underbelly again, which is always awesome, and I had planned to go to Chattanooga. He reached out and said, would you like to come to Soft White Underbelly? I said absolutely, swapped all the plans, and came out to LA.

Owen: Start with who you are in your day job. What do you do at Radial?

Nogga: At Radial, I’m the guy who teaches everybody how to use every piece of machinery we use to give treatment. I train, I teach, and I sometimes treat some of the more complicated or experimental cases, because I’ve been doing it longer than most of our team. Owen’s always been a great mentor and explained everything to me, so I understand a lot of the mechanisms. I also do quality control, making sure people keep up with new information and new ways of using the machines.

Owen: The patient in question had asked to do this. It was her request. She knew I had been on Soft White Underbelly before. Her depression had returned after a prior treatment, and she wanted the world to know she could do better, so she asked for her retreatment to do this. That presented some technical challenges. How did you think through getting a TMS machine to Los Angeles, into a video studio, to do treatment?

Nogga: That was kind of a rigmarole. Neither of us is local, and we had to test the equipment to make sure it worked. We didn’t want any hiccups on the day of. It’s a very simple machine to set up, but if you’ve never done it, you don’t know what to look for. There’s only an indicator light to tell you if things are working.

Owen: A single light on the device! Which system did we choose?

Nogga: We ended up working with the Ampa One because of its portability, simplicity, and versatility. Of all the TMS devices, it has quickly become one of my personal favorites, not just in using it but in teaching people. People get it really quick, especially if they like video games. I flew out a couple of days early. I was lucky the hotel was willing to receive it, and I was close to the studio, so I went over, set it up, and ran through it. Because it was a brand new machine, everything worked. There were no hiccups, and I knew some troubleshooting tricks to recover quickly if there were issues, to keep things on time.

Owen: Not that one is better or worse, but we’ve worked with a bunch of TMS systems. What’s different about delivery of the Ampa One compared to other systems we’ve had arrive at our door?

Nogga: One, it’s small. One person with some strong arm muscles pulls a 40-pound box out of a larger box and plugs some things in. It’s really simple, and everything is controlled via an app on a tablet, which the Ampa team can see live whenever they like, to make sure things are running well.

Owen: They can “zoom” into the device itself.

Nogga: I believe they can watch sessions and see the data live on the back end, similar to how Prism can see what we’re doing remotely. Brainsway, when it’s connected to Wi-Fi, can see the data post-treatment. Ampa can see it while things are actively happening, so if there’s a coding or update issue, they’re a little quicker to respond.

Owen: The original version of the Ampa device we tried used an old MagVenture stimulator. Can you talk about the difference between the production device and the original research device?

Nogga: MagVenture makes a great device. There’s a reason they’re one of the top in the industry. They’re always coming out with amazing software and technologies, and their team is large and has been around a long time.

Owen: We use one of their devices as part of the SAINT system. It’s part of our workflow every day in the clinic.

Nogga: Absolutely, and it’s a wonderful device. But it’s like trying to mix Apple products with Samsung products. They don’t love to talk to each other. Everybody wants you to use their equipment with their equipment with their software. The beta Ampa device worked, but it was buggy, because two different companies were trying to talk to each other.

Owen: In a research setting, still, at the time.

Nogga: In a research setting—There was a lot of unplugging, replugging, and troubleshooting, even in the middle of sessions. Now that’s at a minimum. The most common problem, and I’ve talked to Ampa about this, is a very silly one: the case cover slightly covers the charge port on the tablet, so sometimes the cord can’t seat all the way.

Owen: It’s literally the cover of the tablet, not the tablet itself.

Nogga: It’s a one-millimeter issue, solved by surgically going in with a razor blade and making the hole slightly larger. Then the cable fits fine.

Owen: It’s not on the device manufacturers or the tablet manufacturers. It’s the cover manufacturer. Hashtag supply chain.

Nogga: Exactly, and it’s not all of them. Whenever I see the red blinking light for a cable issue, 90 percent of the time it’s solved by removing the cover and reseating the cable. When you line it up, it’s off by a hair, probably a minor manufacturing defect in the mold. The cable we use is thick because it needs to move data quickly, and the head of that cable just barely touches that piece of plastic.

Owen: So part of your job is having common sense about where things could go wrong, because the most common problem we have with that system has nothing to do with the system. It’s the piece of plastic around it that keeps it safe.

Nogga: It’s a silly engineering problem, and it’s my OCD that lets me catch those little details, which I guess is why you keep me around.

Owen: That and many other reasons. So we get to Los Angeles and get this thing set up. Walk us into the studio Mark has in Malibu. Tell the story of walking in the door.

Nogga: I didn’t realize the entrance was in the back of the building, so I figured that out after standing at the front door for ten minutes with all this equipment and my service dog, and you told me to go around back. It’s a really beautiful old warehouse building with concrete floors, tall ceilings, and skylights, so a lot of natural light floods the space. Honestly, it’s the kind of space I dream of acquiring for my own living situation. White walls and a strangely warm atmosphere, gorgeous leather couches, suede slipper chairs, and of course Mark’s larger-than-life portraits of luchadores and bikers, and even some of his underwater photography from his series on fish, which is my personal favorite. It’s like a gallery, but with a big kitchen and a couple of desks where people work. It feels homey, not clinical or sterile, not the kind of gallery where you feel like you can’t touch anything. They were really nice to let me come in.

Owen: It feels very lived in, probably because they spend a heck of a lot of time there. So we come in that morning. What happens leading up to the videos?

Nogga: We sit down, I set up, and I meet Mia for the first time. She’s having a hard time, but even in her hard time she’s a warm, wonderful person. Really fantastic, bubbly. She reminds me of my aunt, whom I dearly love. Party mom vibes, but also a mama bear, and she exudes that in every word. She’s fun and creative, and we connected immediately. It was easy to be open with her about my own struggle, and we found a lot in common. I explained what I was going to do, and she said she was very familiar. We got out the D-cycloserine, which I had brought from New York in a little baggie in my carry-on luggage.

Owen: It’s a sublingual tablet we have to get compounded specifically for our practice. You can’t get it from a regular pharmacy. It has to dissolve under the tongue to get into the bloodstream fast enough. If we didn’t have literal pharmacists as our head of operations, we might not have the skill set to deploy it. You can’t just prescribe it to a pharmacy and call it a day. We’ve had to source component molecules.

Nogga: Ryan spent a long time finding a compounding pharmacy that would fulfill our order at scale, so we can get it to all our clinics. It’s very precious, so I wanted it on me at all times. It did feel strange flying from New York with it. How do I explain this if TSA or the DEA asks? I’ve been caught with expensive, unexplainable materials before. Flying with equipment for my father, I got stopped at TSA in New York for two hours and almost missed my flight because I had radar equipment on me.

Owen: Oh my gosh.

Nogga: It was a whole thing. I’m used to traveling with a giant magnet, not dissimilar from the magnets in an MRI machine. So I was ready, and it’s just this little tablet. They’re thinking, what do you have, LSD? No, it’s an ancient treatment for tuberculosis. Nothing nefarious, I swear, in an unmarked plastic baggie. But nobody cared. Travel went fine. Maybe traveling with an adorable dog makes you less threatening.

Owen: “Why would a terrorist bring a dog?” (laugh)

Nogga: Exactly. So we got through fine. I pulled out my baggie, and we had 30 minutes to wait. Mia held it under her tongue while it dissolved. Mark came around and asked me some questions about the system, and I explained what Ampa was and what we would be doing with the M coil specifically, M meaning medial and L being the lateral coil. Then you got started with Mark not long after.

Owen: The treatment took place over the course of that entire day. The video compresses it into one hour, but we were there for the entirety of the day.

Nogga: Ten hours, easy. I got there at 8:30 in the morning and we finished around 6:30.

Owen: One thing that’s not obvious: Mia looks completely different at the end, but it’s also the end of what would be, for anybody, a really long day. I probably looked more rundown than she did.

Nogga: She came in crying. Her eyes were red and puffy. She was upset, she was sad, clearly going through it. She was very brave to talk about it and even laugh about some things, which is a credit to her character. A strong person who is very relatable.

Owen: Have you looked at the comments on those videos?

Nogga: I read some of the comments under my video. A lot of positive ones. There are trolls out there, of course. There was a lot of “what’s up, my Nogga,” which is a hilarious joke because of the spelling of my name.

Owen: Oh, Because it’s similar to a racist slur.

Nogga: Yep. Hey, my parents didn’t know how to spell when they came to the United States. I got two G’s and I kept them.

Owen: It could have gone worse. It is a beautiful name. One thing I noticed about both this video and the one I’m in with Mia: compared to other YouTube comment sections, which are not known as a pinnacle of human decency, the ratio of reasonable comments to trolls is shockingly in the direction of the reasonable.

Nogga: A lot of positive comments. There were questions about whether this is covered by insurance, and I went in and answered them myself: that’s something we’re working on. There were also a lot of questions about what I did. It’s funny, because had I known the videos would be separate, I would have done a better job explaining what TMS is. That was my one regret.

Owen: You were a big hit, so I’m sure you’d be welcome back.

Nogga: If Mark (Laita) wants to have me again, I’d be happy to chat more about what we do. Not only do I do it for people, I’m a recipient of it, and it has made huge differences in my ability to function better as an ADHD, OCD, PTSD-having person.

Owen: Knowing what you know from your own experience, how does that inform how you hold hope for the person when you’re administering treatment?

Nogga: One thing I can do is tell them exactly what they’re probably going to experience. When people come in, they’re scared. Like Mia said in the video, and like many of our patients have said: what is this? It feels like science fiction. Is it going to hurt? Is this shock therapy? First of all, this is not shock therapy. We’re not using direct currents. The goal of ECT, electroconvulsive therapy, is to cause a seizure to change the brain. Here, that is what we’re trying to avoid. It’s a one in 30,000 chance you’ll have a seizure, unless you forgot to tell us you’re epileptic, or you come in very, very drunk.

Owen: Or, even more worryingly, very, very drunk the night before, and don’t disclose it.

Nogga: Exactly, which is why we check motor thresholds every day. We did have a situation where somebody quote-unquote forgot they had three to four beers the night before during SAINT treatment, so we had to extend by an extra day. An honest mistake, I guess. But this is why we check motor threshold every day. If I see a ten-point difference, something’s not right, and I go through the troubleshooting list. We got successful MTs before. Why is it ten points higher? Did you have a seizure? Medication changes?

Owen: And the doctor is always looped in and gets to decide what to do, and usually the decision is come back tomorrow. At the end of the day of treatment and shooting, Mark offered you the opportunity to do an interview yourself, and you took it. What was going through your mind in that moment?

Nogga: I’ll admit I was very nervous. I’m a man behind the camera, behind the scenes. That’s how I operate.

Owen: Literally behind the camera. You were a photographer, professionally.

Nogga: Yes, for many years, and I still pick up a lens once in a while for friends. I’m not somebody who seeks the limelight. Even when I was in a band, I used to get terrible stage fright while performing. I did poetry slams as a kid, but admittedly I had the help of substances to make me feel braver, and I don’t use substances anymore. Being in front of people and being vulnerable about who and what I am, knowing there are people out there who don’t like who or what I am for whatever reason, is sometimes nerve-racking. So I was maybe slightly dissociated. I know I was rambling and said “um” a lot, as I’m doing now. When I’m not on camera, I speak quickly and confidently. When the eyeballs are on, it’s a little more difficult.

Owen: What has it been like to have that video out in the world?

Nogga: I’m glad it’s out there. There was a comment from a young trans person that really felt good, and it reminded me why I was in the band I was in, and why I think it’s important to be outspoken.

Owen: That band was an all-trans band, if I remember correctly.

Nogga: All trans, all Jewish, and we sang very silly songs about being gay and trans and Jewish. We were hilarious. Sondheim meets Tom Lehrer meets The Kinks. Absolute shtick rock. But that visibility was important, because there wasn’t a lot of positive visibility of trans people. Being out there, being alive, talking about it, being honest about my struggles and my successes, hopefully shows younger people that they shouldn’t punch their ticket too early. Things can change, and there are opportunities. The work we do plays into that. Queer kids have the highest suicide rates, the highest rates of substance addiction, homelessness, joblessness. And I don’t want this just for trans kids. I want it for everyone, because when you protect the most vulnerable, everybody gets better.

Owen: So the video was, in a way, part of the work we do. Being alive and living a good life as a trans person is a form of suicide prevention?

Nogga: It preserves life and culture and art and everything that comes with that. Every time we lose anybody to suicide, not just a trans person, that’s a light that could have contributed to a better world. That could be the next brilliant musician or engineer, and to lose them because they didn’t see themselves in the world, or because their brain chemistry was a little different and was fighting them and lying to them, as brain chemistry has a tendency to do, is a shame. That’s why I do it. In the video I talked about three of my friends, but really I’ve lost way more than that.

Owen: In a way, living comfortably as who you are is the message of hope you have for the world.

Nogga: Yeah, and I question it myself. I have my dark days. Like I said in the video, a month ago I was doing bad. Really bad. I was incredibly depressed. My partner was worried about me. My parents were worried about me. The saving grace is that I work in this industry now, so I can recognize it, I know my options, and I can access those options. And I’m really lucky I work with you as a colleague and a mentor.

Owen: Not for nothing, shout out to my dear friends at Acacia Clinics, who do a great job with patients. You were able to reach out, find good help, get it to take your insurance, and get it to work. It’s a remarkable thing. Living as our authentic selves is hope-setting, in a way.

Nogga: In the queer community, we say living is an act of resistance. Resistance against anything you want to resist. Against the darkness. You can be political about it if you want, but just living is everything.

Owen: The darkness is all of our enemies. Well, that was a very profound ending, and my children just got home, so I’m going to wrap. Thank you for your time.

Nogga: Anytime, Owen.

And now, the video.

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I called Mark Laita to ask if her wish, to tell the world about aTMS, was possible to fulfill. Mark has YouTube channel with 1.6b views.

He said yes, and our re-treatment took place in front of his camera.

Thanks for reading—it's worth the full watch—the transformation is truly incredible. And thank you, Mia, for your bravery!

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Mia is one of the people who helped build RAMHT with me and Grady, her husband. Our next live event is in September—on the 14th. 5pm in New Orleans.

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BK Historic House and GardensNew Orleans, LA

This is not that. It is FDA soliciting advice from the public on a variety of matters as it applies to all psychedelic medicines.

Below, I share my open comments…

Comment to Docket No. FDA-2026-N-7542

Considerations for Potential Future Therapeutic Use of Psychedelic Drugs; Public Hearing; Request for Comments

Submitted by: Owen Scott Muir, M.D., DFAACAP, FCTMSS Co-founder and Chief Medical Officer, Radial Health, Inc.; author, The Frontier Psychiatrists (thefrontierpsychiatrists.substack.com)

Topic addressed: Section III, Considerations for Access

Disclosure of financial relationships: I am an executive of Radial Health, Inc., a national clinic network delivering interventional psychiatric treatments including esketamine (Spravato) and transcranial magnetic stimulation, and of Neurolief, Inc. I hold financial interests in, or advise, companies in health technology and life sciences, including BrainsWay, Videra Health, iRxReminder, Purple Gaze, Psyrin, Outro Health, Brainify.ai, Acacia Clinics, AMPA Health, Definium, and Atai. I have direct financial interests in the delivery of the class of therapies discussed in this comment.

Summary

The constraint on patient access to FDA-approved psychedelic therapies is likely to be financial. The supply chain that made oral drugs accessible is essentially not relevant to the deployment of psychedelic medicines. It’s crucial the risk evaluation and mitigation strategies as part of FDA labels are designed with the reimbursement landscape in mind. The clinics that become the outpatient distribution centers become the “distribution channel” for these medicines, and as such, it needs to be economically viable for individual clinics and large clinic operators alike to dispense these medicines. I believe it’s in the best interest of patients to make it possible for all operators, not just those already at massive scale, to have access to these treatments. Please consider my comments in that context.

I write from seven years of direct clinical experience. One of my clinics was the first clinic in Brooklyn to dispense esketamine. Radial, the clinical services company that I co-founded, dispenses ketamine and provides neuromodulation, including SNT and Swift across 27 sites in rural and urban locations across 7 states.

Ketamine is the closest existing predicate for supervised and monitored administration of the model, so its reimbursement history is instructive. Contemplated for compounds like COMP360, MDMA, lysergide, ibogaine, and others. .

A. Evidence needs for coverage, benefit design, reimbursement, and payment models

The esketamine model demonstrated, by using existing current procedural terminology codes, reimbursement for consciousness altering therapeutics was scalable. It was possible to get a novel therapeutic to market through a Buy and Bill infrastructure, e.g. the clinics can purchase drugs and dispense it subsequently with some profit margin involved for the operator. The REMS program made this economically more viable because of the high risk being mitigated to the patient by definition (in that 99215 codes are allowed as standard with it’s higher reimbursement because the risk is contemplated in the code). The current consideration of REMS programs should make the duration as clear as the esketamine REMS did. It’s also worth noting that the current “psychedelic therapy” category III codes only allow for up to 6 hours of total monitoring, which may not be enough for the programs you’re considering for some of these compounds.

The REMS program will drive the reimbursement infrastructure. Physician time is a primary cost, but the total practice expense plus physician time that the REMS implies is crucial to consider when crafting the label along with the study sponsor. The current reimbursement infrastructure used by ketamine is a workaround that didn’t involve creating a robust new code set, which will almost certainly need to be the case to encompass all the psychedelic treatments that are coming. I would encourage working closely with your colleagues at CMS to make sure that the code sets and their adoption by Medicare are ready to lead the way along with the FDA approval and the risk evaluation of mitigation strategies as part of those approvals.

2. The billing architecture has a time limit at approximately two hours.

The Medically Unlikely Edit on 99417 is four units per day, which adds only 1 hour to the 40 min of a 99215 parent code (by time). Esketamine is still more time than that ceiling, but only by 20 minutes. Nearly every psychedelic in late-stage development (psilocybin, MDMA, LSD, ibogaine, methylone and more ) all will need complexity based billing and longer monitoring–thanks to the longer acting effects compared to ketamine and esketamine– more similar to surgical procedures than current psychiatric practice.

Absent working closely with CMS, and with the American Medical Association, there is no way to currently bill in outpatient psychiatric practice for a psych medicine procedure greater than six hours. This doesn’t mean your REMS should be limited to anything less than the safest interval, but it does mean that any monitoring for six hours needs to involve coordination with other agencies to ensure it can actually be delivered.

Another workaround would be for those agencies to adopt an oncology-style buy and bill coding around the J, S, and G codes that could be used to account for the dispensing and treatment with these compounds.

This planning cannot be an afterthought. It would be commercially and clinically disastrous for patients to have approved medicines that had no plausible means of reimbursement in the clinic itself, which is the current state of the world in any treatment lasting

3. Recommendation: payment pathways should be established concurrent with approval, not after. Medicare’s creation of bundled G codes for esketamine is an example of a correct template: a single payment encompassing drug acquisition, administration, and the full REMS-defined monitoring period, tiered by dose and session length. Waiting for post-approval rate negotiation, payer by payer and code by code, is itself an access barrier measured in years. Executive Order 14401 directs interagency coordination on access to these therapies; coordinated FDA–CMS sequencing of REMS finalization and payment-code creation is exactly the kind of coordination that would matter most. It would also be acceptable to use the current category III codes for therapy and a G/J Code to account for the “buy-and-bill” activity ONLY, that is likely to be necessary.

4. Recommendation: consider percentage-of-drug-price margin structures and complexity base billing for clinical services.

The experience in oncology of using average sale price (ASP) +6% demonstrates that tying clinician decision-making around the economics of a margin associated with the drug price creates a documented incentive towards more expensive treatments. That said, pairing the reimbursement for physician time to the complexity and risk of the REMS would be more in keeping with traditional “risk based” E+M coding that is the main state of current CPT coding methodology.

I believe that tying reimbursement to the psychedelic REMS program for the particular drug is a viable adjunctive to ASP +6%. The payment needs to compensate the complexity and expense of the service, which of course includes clinical and physician time, monitoring, facility infrastructure, which is well above the traditional practice expense associated with psychiatry, or even neurology, as well as the capital necessary to acquire what are likely to be expensive drugs. These rates need to take into account the fact that these drugs are likely to rise in price, and a drug price multiplier may need to be included in the calculation. This preserves the access that oncology achieved, with broad availability of new treatments without creating unintended incentive to prescribe preferentially more expensive drugs and ignoring the complexity of physician care in the prescribing of these novel compounds.

5. Evidence generation should include delivery-model economics, not only clinical endpoints.

Coverage decisions will require economic data on the cost utility of these compounds, which is very much in keeping with what has been proposed in the TCET program and similar to the log laid out in the not-yet-passed Breakthrough Treatments Act. I believe a version of the breakthrough treatments plan: creating mandatory Medicare payment within three months of approval of the drug, along with mandatory collection of pharmacoeconomic data, and review of reimbursement infrastructure after four years of deployment.

6. Preparation and coordination between providers and payors

Esketamine demonstrated that a lack of operational readiness and a lack of clear reimbursement pathways from payers means years of delay in getting already approved treatments to patients in need. It’s “ramp up time” to commercial viability took years, and that would undercut financial support for these new treatments in the minds of financial markets, thus limiting future innovation.

CMS can lead the way, partnering with FDA, to prepare a code set that would allow for dispensing of these medicines under Medicare rules that will be easier to follow for private payors.

The FDA and federal partners should convene certified sites, third-party payors, Study sponsors, and companies responsible for adjudicating prior authorization to understand what the workflow is likely to be so that it can be expedited.

The definitions around who can prescribe these treatments needs to take into account the fact that all those psychiatrists have the greatest expertise in the management of psychiatric conditions, it may be teams of Psychiatrist and other health professionals, including other physician, practice types that may be involved in the dispensing of these medications.

What is acceptable according to Medicare is likely to be followed by other payors, and thus “getting that right” when it comes to the mandatory standards around physician and clinician licensed type, experience, additional training, certification, and the light can be built into the REMS models and the reimbursement infrastructure.

C. Implementation: workforce, space, scheduling, storage, security, and clinic capacity

A second out capable clinic will require dedicated treatment, per-patient rooms occupied for most of our working dayt, with monitoring personnel, secure, drug storage, compliant with rims and DEA requirements, audiovisual, and IT infrastructure for audit monitoring will also be required.

These are both capital and operating expenses that will be paid by whoever owns the delivery site. Reimbursement needs to take these costs into account. If reimbursement does not count for them, the only entities able to observe the losses will be large, vertically, integrated organizations, the same organizations that have come under significant criticism recently.

Given set and setting are likely to be crucial factors of the deployment of these treatments, I think it’s important to have a collaborative approach around allocating value to appropriate set and setting, as well as as carefully monitoring outcomes.

We want reimbursement models that support payers working with physician owned professional, corporations, and hospitals alike. Independently owned, and physician lead practices are a bulwark against further inadvisable market consolidation, which these medications, rolled out without concern for the underlying economics, could make more common place.

Payment model should be tested against a simple question: can an independent practice deliver these treatments at the rates set for by payers without losing money? If the answer is no, access will narrow, regardless of how many products the FDA approves.

Our published experience with accelerated neuromodulation protocols demonstrates that reducing required visits materially improves treatment initiation and completion without sacrificing outcomes (Hanlon et al., 2026; Roth et al., 2023). The same logic applies to psychedelic delivery: protocol designs, monitoring technologies, and staffing models that increase patients treated per room per week are access interventions, and evidence supporting them should be treated as valuable contributions to the evidence base.

D. Telehealth screening, follow-up, and care coordination

Remote and technology-assisted assessment can extend scarce specialist capacity across the phases of care surrounding the monitored session itself. Two lines of my published work are directly relevant as predicates:

First, validated video-based AI assessment. Our peer-reviewed studies demonstrate that smartphone-recorded, self-administered video assessments scored by machine learning can detect a psychiatric adverse effect (tardive dyskinesia) with reliability exceeding calibrated human raters, including in remote settings (Sterns et al., 2025; Trosch et al., 2026). This supports the feasibility of standardized, scalable remote screening and longitudinal safety follow-up for psychedelic therapies — precisely the data-collection substrate contemplated in Section III of this notice.

Second, passive physiological monitoring during monitored administration. Our proof-of-concept study of a continuous passive monitoring system during 129 Spravato sessions demonstrated high data quality and usability for both patients and providers (Solomon et al., 2023). Technology-assisted monitoring can reduce per-session staffing burden while improving the auditability of REMS compliance — a rare intervention that serves safety and access simultaneously.

Telehealth should therefore be presumptively appropriate for screening, preparation, and follow-up phases, with in-person requirements reserved for the administration and monitoring phase where they belong. Blanket in-person requirements across all phases of care would function as a geographic access restriction without a corresponding safety benefit.

Conclusion

For the first time in psychiatry, a class of medicines cannot reach patients without clinicians and clinical infrastructure in the loop. That is an opportunity to build a delivery and payment system better aligned with patient outcomes than the rebate-driven pharmacy-benefit model it will not use anyway. The Agency and its federal partners should treat reimbursement architecture, session-length billing ceilings, and clinic-level economics as core access questions — because they are the questions that will determine whether approved psychedelic therapies reach the patients the clinical trials were run for.

Respectfully submitted,

Owen Scott Muir, M.D., DFAACAP, FCTMSS

References

• Hanlon CA, Roth Y, Bermudes RA, ... MacMillan C, Muir O, ... Tendler A. Accelerated TMS with the H1-coil for depression: a multisite, randomized non-inferiority trial. Brain Stimulation. 2026;19(2):103050. doi:10.1016/j.brs.2026.103050

• Roth Y, Hanlon CA, Pell G, Zibman S, Harmelech T, Muir OS, MacMillan C, et al. Real world efficacy and safety of various accelerated deep TMS protocols for major depression. Psychiatry Research. 2023. PMID: 37738684

• Sterns AA, Hughes JW, Grimm B, Larsen L, Ma F, Ranjan R, ... Muir OS. Detecting tardive dyskinesia using video-based artificial intelligence. Journal of Clinical Psychiatry. 2025;86(3):25m15792. doi:10.4088/JCP.25m15792

• Trosch R, Sterns A, Grimm B, Larsen L, Talbot B, Ma F, Ranjan R, MacMillan C, Hughes J, Friedman J, Muir O. Cross-dataset evaluation of an automated video-based model for detecting tardive dyskinesia using the Clinician’s Tardive Inventory: validation study. 2026. PMID: 42133936

• Solomon N, Hajduk M, Majernik M, ... Muir O, ... Karlin D, Barrow B. Evaluating passive physiological data collection during Spravato treatment. 2023. PMCID: PMC10716422

• Feyder, M. T., Stimpson, K. H., Geoly, A. D., Ford, T. J., Maron-Katz, A., Lutkenhoff, E., ... & Bentzley, B. S. (2026). Real-world evidence of SAINT® effectiveness in a heterogenous clinical population with psychiatric and medical comorbidities: A multicenter, open-label, community-based study. Journal of Mood & Anxiety Disorders, 14, 100184.

Thanks for following along. I can’t emphasize enough how much open comments matter in our crucial regulatory process—your voice matters!

A special thanks to Kenneth Shinozuka, Ph.D. for his collaboration on the editing of the comments.

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You can find this gracious doctor, and his practice, at the links below:

Randy I. Pardell MD DLFAPA, FCTMSS

Chief Medical Officer, Clearwave Mental Health

President, Foundation for the Advancement of Clinical TMS FACTMS.org

I would also strongly encourage donations to FACTMS.org. They are bringing awareness of treatment and supporting research and clinical care for those without means. If you believe in the work that I write about, and want to make a donation? This is a great organization to support!

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The news keeps being hot leading up to this event…

• Former speaker Dr. Joshua Brown is the first Head of Brain Medicine.

• Radial is Scaling.

• Salma Health is offering specialized treatments for depression, anxiety, and even headache and facial pain. They are also hiring a ton!

• BrainsWay accelerates its transdiagnostic potential with studies in stroke and a great feature video featuring Speaker Colleen Hanlon, Ph.D.—who will be doing an “ask the expert” opening to the event:

• Psychiatric Times covers Brain Universal’s FDA cleared system for dry EEG in clinical practice.

• EyeThree talks publicly about their qFMRI technology.

• Definium’s Phase III Voyage Trial toplined!

• Neurolief launches support for prescribers for patients using commercial insurance for ProlivRx— an at home treatment for depression after only one prior medication trial.

Enjoy the interview between myself and Grady below, where we talk about what's coming.

Stay tuned, get excited for more & see you in New Orleans! Also, we will have special guests. And surprises. And maybe….embarrassing merch, for me, personally.

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Owen Muir: We have another Rapid Acting Mental Health Treatment event coming up. Introduce yourself to our readers.

Grady Hannah: I’m Grady Hannah, co-founder of RAMHT, and I’ve been in psychiatry and digital therapeutics for over 10 years. Extremely excited for the upcoming event in New Orleans on September 14th.

Owen: We’re finally bringing RAMHT to the Big Easy.

Grady: Yes. A great local presence, plus people coming from all over. It’s our first show in New Orleans and we can’t wait.

Owen: Give the audience a little backstory on why It it was a great idea to bring this event to the big easy, and to open the invitation to professionals more broadly than just the psychiatrists who tend to attend APA?

Grady: The psychiatric nurse practitioner network is growing fast, and they’ve got a unique, pragmatic perspective. We have Andrew Penn as a speaker, one of the real stalwarts of that community. Many psych NPs come from other disciplines, so they bring practical experience relevant to psychiatry, or a different set of values that improve the care paradigm in ways that aren’t always obvious.

Owen: One example from my own experience. Guess how many blood draws I had to do in my medical school curriculum?

Grady: Zero.

Owen: Correct. I did dozens, then hundreds, through an elective emergency medicine procedure club. When I got to residency at Northwell, there was no weekend phlebotomist, and my classmates, with the standard zero venipunctures, were really lost. I wasn’t. A prior career in nursing or PA training gives you, I hate to call it more practical experience, but it’s more practical experience. What else makes nursing a great prelude to a subspecialty like psychiatry?

Grady: This is a group building their own practices. Psychiatrist MDs may be further down the rabbit hole of the cerebral and behavioral sides of the mind. Psych NPs look more at patient care and clinical operations, a little more patient-centric, and explore complementary areas of care to create new practices. I have my ideas about what this audience will be like, but that’s part of the excitement of a constituency that differs slightly from APA. I’m sure a lot will be familiar too.

Owen: This is also the first RAMHT meeting with robust, shareable data: finally, top-line phase three data on lysergide D-tartrate, otherwise known as LSD, from Definium’s Emerge study in major depressive disorder and Voyage study in generalized anxiety disorder. For the first time we’ll know what double-blind, randomized controlled trials look like. How does the data look to you?

Grady: The depression data is really powerful and has had a big impact. You see a lot of excited discussion. The anxiety data is very powerful too, but more overlooked. That’s what excites me, because it’s as if we’ve all decided that anxiety, even severe anxiety, is acceptable. And there aren’t great treatments for it.

Owen: Maybe that’s why we tolerate it. We have drugs we literally called antidepressants. Any clinician knows they often work, somewhat, for anxiety too, but even the name was antidepressants. Panic disorder got an FDA label; generalized anxiety disorder just didn’t have much of anything. And if you have nothing, it doesn’t make sense to focus where you can’t do any good.

Grady: Excellent point. I’m also very interested in the implications of LSD treatment. How are people going to be cared for during their treatment?

Owen: It’s a whole different business. They’re there for hours in a row.

Grady: And it’s coming soon.

Owen: Speaking of which: literally today, a secondary analysis from our colleagues at BrainsWay, from the SWIFT trial I was involved with, demonstrated rapid reductions in suicidality with accelerated deep TMS. The paradigm is similar: five hours a day for six half days, much like a psychedelic dosing day. Analysts are hand-wring about spending more than two hours in a clinic, but accelerated TMS patients have spent all day there for years, and it’s better for reducing suicidality. Relevant for this audience?

Grady: My wife, Mia, who’ll be speaking as a TMS advocate at the event, had a significant remission in her depression from an intensive one-day TMS treatment. Where LSD patients spend their treatment may look different than a typical clinic, but people are there for a therapeutic purpose. For many disease states, people have hospital stays much longer than a day. When you do the cost-benefit analysis, you fit the treatment to the cure. If that’s what’s necessary, we’ll adapt, as long as the data keeps looking this promising.

Owen: It’s like a good enterprise software pitch: they discuss your investment in the product, not your purchase. We’re investing time in remission from debilitating conditions. Framed as an investment in feeling well, it’s a little less hand-wringy.

Grady: They also talk about amortization. Intensive treatment over one day with a profound effect on your well-being likely beats taking an SSRI for years or decades.

Owen: And no one gripes about how long you spend on the golf course. Plenty of things get a full day and a blocked calendar.

Grady: Right. There’s a lot of movement in this space, and we want to keep current from the clinical, patient, and macro perspectives. You and Carlene are fantastic partners, and I can’t wait for the event.

Owen: I’m thrilled to say more soon, because we didn’t touch on novel diagnostic adjunctives: EEG and fMRI to understand what’s going on inside the brain before, during, and after these treatments.

Grady: It’s really two complementary categories, treatment planning and objective diagnostic analysis. TMS targeting, understanding the effects of TMS pulses on the brain: it’s important quantitative data, because as an industry we want objective inputs and outputs that show standard of care, so psychiatry gets payment schedules representative of interventional brain medicine using state-of-the-art tools. There are newer, vertically integrated companies in dry EEG (hardware, software, and diagnostic), plus traditional players finding their way. A lot of intersection happening.

Owen: I look forward to folks joining us September 14th in New Orleans to learn about these rapid, and more importantly, more effective, treatments and diagnostics for brain disorders.

Grady: Can’t wait, and be there early. The first attendees are entered in a raffle for a limited edition Owen Muir bobblehead. If you want a little more Owen in your life, it’s possible. Not life-size, unfortunately. Please join us.

Owen: The pint-size Muir bobblehead is real, and prompt arrival enters you in the raffle. This is so embarrassing.

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BK Historic House and GardensNew Orleans, LA

Monday, September 14 • 5 PM - 9 PM

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I present it for posterity, and for those who want to see inside the disagreements in my peculiar marriage.

I’m not a venture capitalist. I’m not an investor. I don’t have much money to my name. I’m a doctor, and I started my career later than most. I enrolled in medical school at age 27, graduated at 31, did four years in general psychiatry residency, and a two-year child psychiatry fellowship after that.

That would’ve been foolish enough, financially, except I started trying to build businesses. This is the story of the businesses we should build to ensure a better world with more effective treatments for psychiatric patients.

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Here’s what I noticed: pharmaceutical and device companies will only keep creating miracles if they make a hell of a lot of money doing it. Doctors need to get in the middle of that process and get paid like the valuable members of the system they are, instead of watching all the money go to pharmacy benefit managers and other conglomerates.

Cut the doctors in. That’s the argument. The rest is the math.

Full disclosure, before the math: I’m a C-level exec at Radial and Neurolief, and an advisor to companies in health tech and life sciences. I’m arguing “my own book.” Feel free to discount my opinions accordingly.

The old way: doctors as a free distribution channel

Take a pill with a wholesale acquisition cost of $100. The pill itself costs pennies; total cost of goods is $1 to $10. The wholesaler takes $2 to $4. The pharmacy benefit manager takes a “rebate” of $25 to $50 in exchange for a better formulary tier and a lower co-pay. PBM and group purchasing fees eat another $3 to $5. Then there’s co-pay assistance — the manufacturer buying down the price at the register so the customer doesn’t walk away. It doesn’t make the drug cheaper for the health plan the customer is also funding through premiums; it just feels like it does. Add the salespeople and the TV ads, and it costs the manufacturer $50 to $70 just to get the drug into the medicine cabinet.

The profit is still tremendous: roughly $30 on every $100 of list price. 30% margins is a pretty good business.

You know who makes none of it? The doctors prescribing the pills. I know it sounds crazy, because we all know doctors are on the take, but really, we’re being plied with praise, pamphlets, and the occasional two-thousand-dollar speaking gig — while generating massive profits for the drug companies, the PBMs, the pharmacies, and the insurers. Everyone but ourselves. We are a free distribution channel.

The alternate universe: buy-and-bill

Spravato was the first of the “in-clinic medications” in psychiatry — my old clinic was the first to dispense it in Brooklyn. In buy-and-bill, the practice contracts with a specialty distributor, purchases and holds the inventory with its own money, administers the drug on site, monitors the patient on site, and bills the patient’s medical benefit rather than the pharmacy benefit.

The billing is a thicket. Medicare bundles the drug, the visit, and the two hours of observation into single codes (G2082 and G2083, tiered by dose). Commercial plans typically require an S code instead — S0013, esketamine per milligram — plus separate billing for the clinical time: an E/M visit with prolonged-service or staff-observation add-ons. And there’s a hard ceiling: a Medically Unlikely Edit caps the prolonged-service code at four units, so the whole scheme stops working past two hours.

Now the squeeze. Drug prices go up every year. Physician reimbursement, against inflation, goes down every year. So the doctor buys an increasingly expensive drug and gets paid a shrinking amount to administer it. The alternative is to skip the inventory risk entirely: order from a pharmacy — often owned by the PBM, which is owned by the insurer — bill your standard rate, and let them work out the math on the back end. UnitedHealth’s Optum employs about 10% of American physicians and owns OptumRx and specialty pharmacies like Genoa, which handles most of the Spravato business. United negotiates with itself, then with itself, then with itself again, to divvy up the money.

The independent physician gets squeezed either way.

The part where you tell me this is a terrible idea

Yes, I know about oncology. Oncologists have bought and billed infusion chemotherapy for decades — that’s where the permanent J codes come from. Medicare pays average sales price plus 6%.

Six percent of a $500 drug is $30; of a $15,000 drug, $900. You can see how a thoughtful physician, reviewing the evidence, might conclude that the more expensive drug is, on reflection, clinically superior. Congress noticed. Your premiums noticed. “Buy-and-bill” became a phrase you say at a health policy conference if you want people to look at you with disdain.

The psychedelic version is different — not because of our inherent virtue, but because these drugs come with guardrails: Risk Evaluation and Mitigation Strategies. Spravato’s REMS requires monitored, in-clinic dispensing. I can’t infuse a patient with extra ketamine to make more money. The dose is the dose, the observation window is the observation window, and the certified clinic is accountable and audited for both. Compare that to the rebate maze above and ask yourself which incentives you’d prefer: tiny-pill rebates to the tune of billions, or physicians incentivized to provide treatment that’s more likely to get patients to remission.

The leverage

The pipeline drugs behind Spravato — psilocybin, LSD, MDMA — will almost all require longer monitoring than we can currently bill, and none of them will go through a retail pharmacy. You can’t roll up to your local CVS and get handed a bottle of psilocybin with a sticker that says “may cause ego-dissolution.” These treatments are in-clinic by design. The clinic is the distribution channel. Those clinics need rooms — with cameras, IT infrastructure, furniture comfortable enough for a full day of treatment — and whoever pays for the rooms owns the economics.

There are two candidates: physicians, or the conglomerates already acquiring us at a rate of about one in ten.

For the first time in my career, the drug can’t get to the patient without us. That’s leverage. Pharma needs certified clinics the way it used to need a pharmacy’s shelf space. At long last, we are the scarce resource.

Doctors are terrible at business — I should know, I’ve been pretty terrible at it myself. We can stay terrible, and Optum and its colleagues will happily handle the details and pocket the dollars without us.

Or we can get good at business while we still have the leverage. I’ve made my choice; you’re reading it.

This essay exists so you make yours.

If not for ourselves, then for our patients. I’d bet they’d prefer the set and setting of a clinic owned and operated by physicians over the set and setting you’d expect from the companies that brought you “prior authorization is not a guarantee of payment.”

P.S. This is urgent in a way with a deadline attached. The FDA is considering how psychedelics get regulated before any of them officially have been, and there’s an open comment period coming up on September 14th.

The submit link? It’s in green on the top right!

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Editor’s note: the original version of this was twice as long and twice as detailed and my wonderful wife told me it was boring and unreadable. I asked her to edit it and she declines. Thus, to placate her, I had Fable 5 cut half of it. The above article is the result of that collaboration between man, wife, and machine. I’m gonna drop the un-Fable-edited version in a subsequent subscriber-only post and you can feel free to compare and agree with my wife.

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Join us at our next Live RAMHT event—on the opening night of Psych Congress, September 14th!

Sponsors include:

Definium Therapeutics, BrainsWay, Salma Health, Neurolief, MDHub, Axsome, Universal Brain & Radial

The Tickets to the event are now FREE!!!

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Our theme — Building the Practice of Tomorrow, Today — reflects our ongoing efforts to transform the future of brain medicine, accelerate access to innovative mental health treatments, and foster a community of experts and advocates dedicated to improving lives.

Led by me, Dr. Owen Muir, and my team mate in life, Dr. Carlene MacMillan, of this very The Frontier Psychiatrists Substack – along with Grady Hannah, Co-Founder of NightWare and RAMHT – the event aims to connect audiences with the leaders shaping the future of psychiatry through:

• Rapid-fire 1:1 talks daring to ask the big questions and address the elephants in the room.

• Conversations focused on where interventional psychiatry is heading and how scientific discovery is being translated into real-world impact.

If you’re a nurse practitioner, psychiatrist, psychologist, researcher, resident or advocate, stop sitting through the usual, dry panels!

Join us for an engaging evening of discussions focused on breakthroughs in mental health care that are guaranteed to be both entertaining and impactful.

Speakers who’ll help us explore a range of advancements in rapid acting mental health treatments include:

• Jessica Malberg, PhD, Executive Director, Medical Affairs, Definium Therapeutics

• Colleen Hanlon, PhD, VP of Global Medical Affairs, BrainsWay

• Andrew Penn, RN, NP, CNS, PMHNP-BC, Director of Clinical Nursing Operations, Salma Health

• Kate Passanisi, MBA, Managing Director, CareNetGPO

• Tobias Marton, MD, PhD, Chief Medical Officer, Mindful Health Solutions

• Steve Beller, Chief Commercial Officer, Neurorelief

• Kazu Okuda MD, Founder & CEO, Universal Brain

• Jay Pathmanathan MD, PhD, Medical Director, Beacon Biosignals

• Prantik Kundu, PhD, Co-Founder & CEO, EyeThree

And many thanks to our sponsors Definium Therapeutics, BrainsWay, Universal Brain, Radial, Salma Health, Neurolief, mdhub. Not only are they working tirelessly to transform the future of brain medicine, but they are instrumental partners in making RAMHT possible as a live forum.

So, block your calendar for September 14^th and grab your FREE ticket via Eventbrite!

We’ll be sharing more details on speakers, rapid-fire talks and panel discussions on the RAMHT website and LinkedIn page (follow us if you’re not!).

Stay tuned, get excited for more & see you in New Orleans! Also, we will have special guests. And surprises. And maybe….just maybe…embarrassing merch, for me, personally.

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Prior RAMHT-themed content includes:

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Yes, I've seen that study. How do I get through all the research? I use some simple tricks to save a lot of time. I'm going to share some of them with you today!

A Brief Message from our “Live-Events Motion:” Join us at our next RAMHT event—opening night of Psych Congress, September 14th!

Sponsors include:

Definium Therapeutics, BrainsWay, Salma Health, Neurolief, MDHub, Axsome, Universal Brain & Radial

The Tickets to the event are now FREE!!!

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Science articles have a predictable format. The first thing I do is…

NEVER READ THE WHOLE PAPER.

Yes, really.

Original Research has the following format:

Abstract: Read this.

Introduction: Do not read this.

Methods: Read this carefully! If there are no red flags…

Results: Read this!

Discussion: Don’t read this.

Conclusion: Don’t read this.

I have just reduced the amount you need to read by a lot.

Abstract: This is very short. It will summarize what the rest is about.

Introduction: Do not read this. This is fluffy background. If you want to learn to write papers, you will need to read some of these. But no science is happening in the introduction.

Methods: Read this carefully! It helps us understand what the article might be able to demonstrate. I promise you; it is the only mandatory section1. I will help you with tips that require no knowledge of the subject matter. They are all about formatting and spot-checking for bs. There is a lot of bs in Science. I promise you— not finishing an article that is bullshit has zero penalty. Not finishing a groundbreaking article— erroneously—also has zero penalty! Others will replicate it, and you will see it again!

You Results: Read this! If the methods pass the “sniff test” for bullshit, the findings are in this section.

Discussion: Don’t read this. This is SPIN. This is the authors explaining what they want you to think. You don’t need their help. Are the methods real? Are the results significant? Are they significant…and big enough to care about? YOU WILL ALREADY KNOW THIS by the time you get here. You don’t need their bias, and it’s not worth your time.

Conclusion: Don’t read this; they said it above.

More time savers!

A paper must first establish the clinical trial was a study of causality. This necessitates successful randomization. This means every reputable research study will have the same table one.

Table one is our double check on if the randomization was successful.2

Table one should include baseline demographics like this:

Table one has this format…

I don't know even need to know the field of medicine! I’m only asking a “there/not their question” to start.

TFPs (Patent Pending) Fast Lane.

No table one? Ignore.

But what if I know nothing about this science and it looks interesting?

I know nothing about that modality. But I am going to be ok, cause I need to look at Table one first:

Why are they showing me data about the sham and active intervention in “table one?” That is not what goes in table one. I get it; there is a very significant P value! But it doesn’t go in table one.

Ignore this study.

But it might be groundbreaking!? Yes. And then it will be replicated by scientists who know how to write a paper.

I can’t answer the question, “Can XYZ intervention cause this difference”— because I don’t know if the randomization was successful. I’m sure very prestigious journals won't waste my time this way…

Moving on to table two…the following is just my favorite quote from a journal in a while, forgive me:

To prevent the audience from getting bored while reading a scientific article, some data should be expressed in a visual format in graphics and figures rather than crowded numerical values in the text. Peer reviewers frequently look at tables and figures. High-quality tables and figures increase the chance of acceptance of the manuscript for publication.

Yes, peer reviewers do look at those tables! We do, we do! They continue to point out some important details:

I feel so seen!

Table one is supposed to include baseline stuff. This includes demographics and clinical characteristics. The two groups must be the same at baseline—no significant differences. If there are significant differences, they were not successfully randomized! We can stop reading right there! Because, and this is important—

IF THE TWO GROUPS ARE DIFFERENT AT THE START AND DIFFERENT AT THE END, HOW CAN WE KNOW THE INTERVENTION DID ANYTHING?

We can not. I’m serious. Stop reading—next paper. No information about causality can be inferred.

Here is my favorite classic example, as Published in the American Journal of Psychiatry. The headline for the study was…positive.

If this newsletter has a slogan it might be “helps do what and for whom?” My argument is based on needing to know nothing about science.

Here is the title of the paper:

We read the abstract. Nothing special. What do the figures look like?:

Owen, that graph is from results! Methods first…In table one, they presented demographics:

I am annotate my issue. We can basically stop reading the paper now. But you won't. This will prove my point about wastes of time:

Table two looks fishy. First off, it’s more baseline date. That goes in table one! This is table one.2, not table two! And hold on…

The intervention group was sicker at baseline. regression to the mean is a real statistical phenomenon—they will get “less sick” by chance alone.

The difference shown in the results:

Nope. It’s what happens when your randomized controlled trial about an intervention has the veracity of a Harlem Globetrotters Basket Ball Game Referee—the outcome was not because they won the game…it was a setup.

Now, we parsed that thing way more than we needed to. We should have stopped at “table one and two are actually table one and that ain’t right!”

This is the kind of rapid assessment and analysis that lets anyone—expert in the science or not—quickly dismiss papers that are unlikely to have useful conclusions.

This paper is of course a classic cautionary tale. It was such a bad study that it got a whole write up in the times!

Here is how absurd the behavior that led to the data was…

Two of the study participants were living in a residential treatment facility for sex offenders and may have lied about their diagnoses to qualify for the trial. One of those men slipped the drugs to unwitting treatment center residents and staff, an alarming development that nevertheless did not seem to ruffle the university oversight board that is charged with looking into such episodes.

And even more horrifyingly absurd:

Spiked Oatmeal

One morning in May 2010, residents and staff members at Alpha Human Services, a residential treatment facility for sex offenders in Minneapolis, sat down to breakfast and noticed something strange about their oatmeal. It was pink.

I think we can all agree that drugs given in the oatmeal of non-study participants is unlikely to be effective in the treatment of anything other than “disorders of oatmeal flavor by proxy”?

That is nightmare behavior in a research study. However, you did not need to know any of it.

We could have avoided wasting time on that paper! Just use the TFPsFastLane approach.

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[we come to] learn the incomparable lesson of calm and scientific intelligence, of its systematic application to the improvement of the social conditions and to the refinement of the beauty of the soul and the body. In the harmony of lines and attitudes, the rhythmic grace of gestures, and the balance of thoughts, one would recognize the god of Delos, passing in his chariot, joyful and full of promises.

—Antonio Egas Moniz, Nobel Prize Winner in Medicine for the Lobotomy, on his Journey.

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In psychiatry, we spend much time focusing on the side effect profiles because most medicines don't work very well. Unfortunately, that's just the truth.

The unfortunate side effect of this educational and informational approach is that we spend much more time communicating the risks of treatment than the benefits of being well.

We underemphasize the risks of being crippled by a psychiatric illness. We avoid difficult conversations about trade-offs to avoid confrontation with the dangers of a life that sucks. We didn’t start that way.

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The Nobel Prize in Medicine has been given to two psychiatric interventions.

The first was awarded to Austrian psychiatrist Julius Wagner-Jauregg in 1927 for his discovery of malaria treatment for neurosyphilis or general paresis of the insane (GPI). The second was awarded to Egas Moniz, the inventor of the controversial lobotomy procedure, in 1949.

The malarial cure for insanity was biohacking at its finest. Treponema Pallium, the spirochete behind the disease syphilis, is a very complex bug. It starts as a sexually transmitted infection but rapidly disseminates throughout the body…and after 20 years or so, it’s drilled enough holes in your brain that you go mad. This is an obvious simplification of a complex host/parasite relationship, but the essential feature about the lil’ Treponema is that they don’t love a sauna. They die above 104 Degrees Fahrenheit. And malaria, well, that causes fevers up to 105.

And 105, well, that’s an autoclave for your neurosyphilis. So by giving people one of the leading causes of “insanity” at the turn of the century, malaria, you equipped them with the ability to generate fevers so high they cured their syphilis.

If this sounds like a horrible idea, it pales before the horrors of late-stage syphilis:

The incidence of neurosyphilis increased significantly during the 19th century and was one of the major factors in the increase of the asylum population during this time. Approximately 5 percent to 10 percent of all psychiatric admissions before 1945 were attributed to neurosyphilis; therefore, these individuals comprised a significant group within the asylum population [13]. In addition, the disease predominantly afflicted middle-class males, and the symptoms were obvious: paralysis in conjunction with dementia or psychosis. Once the patient became symptomatic, the end was near. Death, in most cases, was welcomed as the final respite from the horrifying symptoms of neurosyphilis. Consequently, malarial treatment played a role in the emptying of the asylums and provided a viable alternative for a previously hopeless disease.

It was a moment for biological psychiatry. The second Nobel in Psychiatry continued in this interventionist theme: The inventor of the Lobotomy was Portuguese neurosurgeon Antonio Egas Moniz. The doctor had this to say (translated from his native tongue to English) on the advent of his award with The Nobel:

Intelligence and creative power are always wonderful gifts, but when joined with the spirit of sacrifice and selfless dedication to human happiness, their superior beauty shines with divine light.

Men of science, especially medical scientists, know that truth is elusive and absolute happiness is unattainable, but they spread their wings of thought in an effort to alleviate human suffering. In the chaos of misery and sorrow, they pass like a glimmer of hope, tenacious, anxious, and persevering. For them, for their positive spirit, the general regime of nature is governed by an inflexible order, and no prayer can alter it. Only the perspicacity of their intelligence can reveal to them some partial truths. "They look upon the mystery of things as if they were God's spies."

These innovators were not barbarians, nor were they hucksters. We did not have better treatments. And we needed them. We need them still. There have been few innovations at the scale of “10% of patients cured.” We learned to settle for “half as sick," and the siren song of the provably improved became irresistible. Evidence-based medicine is excellent… until we start asking, “to what standard of evidence must we hold our healing?”

I regularly argue, relentlessly, so much that I should shut up already, that we need a higher standard for what treatment should accomplish for our patients.

The gold standard of “good enough” in scientific research in the treatment of depression has been a 50% reduction in symptoms as measured by a rating scale by a blinded rater to treatment condition, like the MADRS or the Hamilton-D. In schizophrenia, that standard is less still: it’s a 20% reduction in symptoms on the PANSS. Why is it less? Well, it turns out the guideline-making is maddeningly opaque. Without that lower bar, we’d rarely have an approved treatment. So, we lowered the standard. The soft bigotry of low expectations isn’t just a hit line from a Bush-era speech writer; it’s a professional ethos inadvertently.

The flip of a coin is an evidence-based treatment to pass the time. It improves winning a bet when you call “heads” in 2.5% of studies on the topic— if one was foolish enough to believe the statistical chance demonstrated a real difference.

The interventional approaches of the early biological psychiatrists were not effective in the most severely ill patients who have schizophrenia (from John Crilly’s brilliant paper on the history of clozapine):

A number of controversial pharmacologic (e.g., insulin shock therapy) and physiologic (e.g., prefrontal lobotomies) attempts were made to treat symptoms of schizophrenia, none with any notable success. Although the process and results of such interventions were often tragic, professionals working with the most seriously mentally ill during those times had virtually no treatments at their disposal. Pharmaceutical companies, too, had little success in developing medications to treat schizophrenia on a large scale.

We would do well to remember that helping those suffering is difficult—for those trying and failing to help.

To quote Tom Main from 1957, in the classic The Ailment:

“When a patient gets better it is a most reassuring event for his doctor or nurse…cured patients do great service to their attendants…we know that doctors…undertake the work of alleviating human suffering for deep personal reasons and that the practice of medicine, like all human activity, has abiding unconscious determents…we need not be surprised if hopeless human suffering tends to create in ardent therapists somewhat the same gamut of feeling.”

The challenges we set forth to confront with our patients are existential and horrifying at times. Our focus has long been on doing something. But what that something could accomplish needs to be clarified. That something might be a shared expression of the stuckness of a hopeless moment. Absent this, we often descend into the potential sadism of the next thing to do unto another. We do this more often than we might like. We avoid our powerlessness, and, in so doing, relinquish the power of bearing witness to the true.

—Owen Scott Muir, M.D.

Disclosures: I am a child and adolescent psychiatrist and a past prescriber of the first-generation Monarch device. I also work with Neurolief, a company that makes and eCOT-AS device for depression and another one for migraine—that’s a trigeminal and occipital nerve stimulation device, which puts me in an adjacent part of the neuromodulation field, although not “direct competition.”

I think my readers deserves to know that going in. I am enthusiastic about this technology, and I have skin in the broader game—I’m also a cofounder at Radial, which prescribes these devices. I have no equity in Neurosigma, and receive no compensation from them.

Owen Muir: It is great to talk to you again. Feel free to introduce yourself for our readers.

Colin Keeley: My name is Dr. Colin Keeley. I am the CEO of NeuroSigma, and we are commercializing the Monarch External Trigeminal Nerve Stimulation System, the Monarch eTNS system, for treating pediatric ADHD. About two weeks ago we launched the second-generation version of the Monarch device in the United States.

Owen Muir: I am excited to talk to you about this, for both personal and professional reasons. But I want to start with the origin. I had a conversation recently with our mutual friend, and the creator of eTNS as a modality, Ian Cook. Can you walk me through what Dr. Cook did to work out that stimulating the trigeminal nerve, and specifically trigeminal nerve division one, so it sits on your forehead, could change the brain? How was that figured out originally?

Colin Keeley: It is an interesting story, and like a lot of invention stories, there is some serendipity and luck along the way. The original concept for TNS was to use it as a treatment for drug-resistant epilepsy. That was thought of by Dr. Christopher DeGiorgio, an epileptologist at UCLA who did a lot of work with vagus nerve stimulation, back when that was not even FDA approved as an implantable treatment for drug-resistant epilepsy. He conceived of this noninvasive cranial nerve stimulation modality as an alternative to an implantable vagus nerve stimulator, and he started running clinical trials, both open-label and then a blinded study. One of the consistent points of feedback was that people were coming in and reporting mood improvements, improved clarity of thinking, better sleep, deeper sleep, things like that.

Owen Muir: They were both at UCLA. They were probably down some kind of hall from each other.

Colin Keeley: Correct. So DeGiorgio took those clinical observations to Dr. Ian Cook, a psychiatrist at UCLA who specializes in the treatment of adult depression. Ian was very interested, because he was a pioneer in the use of transcranial magnetic stimulation, and he felt that TNS could be a nice addition to the armamentarium. One of the cleverest things Ian did right off the bat was a small PET study, which was published about nine months ago, though it took a while to get out. It was a small PET study in adults with major depression. It was an acute study. They had never received TNS before. He used an on-off treatment paradigm, something like six scans, three with TNS on and three with TNS off, and then analyzed the scans for areas of significant activation and deactivation. It was really interesting, because there was a dual mechanism that was not necessarily anticipated.

Owen Muir: So in the temporal region, the hippocampus, you saw changes in regional cerebral blood flow, which is a proxy for electrical activity. Because this is positron emission tomography, they are using a radio-labeled tracer, correct?

Colin Keeley: This was O-15 PET.

Owen Muir: So this is radio-labeled oxygen. It is the PET analog of the BOLD signal change you would see in functional MRI.

Colin Keeley: Correct. Sorry for getting into the weeds a little.

Owen Muir: No need to apologize for getting into the weeds! I want to make sure we get it right. We are measuring the fact that if the brain is more active, it is using more oxygen. Cells need oxygen to function, so they used specially labeled oxygen to follow how it is being utilized in the brain. And in the hippocampus, the memory center, at least for short-term memory, you saw increased activity, and...

Colin Keeley: Actually, that was an area of decrease. The hippocampus and the temporal regions showed decreased activity.

Owen Muir: Challenging my preconceptions!

Colin Keeley: What is interesting about that is that the temporal lobe is the most common anatomic area where seizures originate.

Owen Muir: Right. Temporal lobe epilepsy, hippocampal seizures, things like that.

Colin Keeley: And then conversely, there was a significant increase in blood flow to regions of the prefrontal cortex.

Owen Muir: So you saw a change that challenged your preconceptions.

Colin Keeley: Absolutely. This dual mechanism of action was not expected. Parts of the brain light up, parts of the brain decrease. We think the decrease explains the anti-seizure effects, and the increase explains the cognitive and mood effects.

Owen Muir: It may be that these things are related, and this is speculative, but we may be remembering differently when we are depressed. And these were depressed people.

Colin Keeley: That is a great point. I agree.

Prior Articles on the Topic include:

Owen Muir: Let us backtrack a little and just explain the technique itself. External trigeminal nerve stimulation, which is what we can put people in a scanner and watch change the brain. What is it, and how big of a deal is it to get this treatment?

Colin Keeley: This is not an advertisement, this is my opinion as a physician: this is a very benign medical treatment. You have the trigeminal nerve, the fifth cranial nerve, which primarily provides sensation to the face, although it is a lot more complicated than that. You apply an electrical patch to your forehead, and that patch stimulates the V1 branch of the trigeminal nerve, bilaterally, on either side of your head. When I say stimulate, we are using very low levels of electrical current, generally between two and three milliamps. The patch connects to a little box smaller than a cell phone, the pulse generator, which administers the current with a specific proprietary waveform and treatment algorithm. In the clinical trials, children with ADHD did this overnight while asleep. They take it off in the morning and go about their day. It is a pretty easy therapy to integrate into your life.

Owen Muir: There was thinking behind the overnight schedule originally. Can you take me through that? It sounds like it is basically a less nasty Band-Aid, easier to get on and off than a Band-Aid.

Colin Keeley: Yes. On the nighttime piece, we have to go back to the early days when DeGiorgio was working with epilepsy patients and comparing his approach to implantable vagus nerve stimulation, which works 24 hours a day. He asked himself, how do I get people to use this as much as possible? He is just trying to prove it works. And he decided to have them use it overnight while asleep. That paradigm worked for us, so we carried it forward, because it does not interfere with people’s day. That said, one of the things we are working on, and I do not want to get ahead of myself, but we think we will soon announce a clinical trial where people would use the device for two hours in the evening rather than the eight-hour overnight paradigm. It is possible that eight hours is overkill. We honestly do not know yet. So that is something we are trying to figure out.

Owen Muir: It is an answerable question. You had a paradigm that worked, and you went with it. So you stick a sticker on the forehead, it has some gel, it hooks up to a pulse generator, and that is the whole medical device.

Colin Keeley: That is the whole thing. And we have never had a serious adverse event. I believe it is a very safe medical treatment.

Owen Muir: That is great to hear. The FDA label for this is in kids. What is a kid in this context?

Colin Keeley: It is a patient seven to twelve years old who uses the device as monotherapy for treating ADHD.

Owen Muir: Monotherapy. That is a big deal, at least from my perspective as a child psychiatrist, because it means you do not necessarily have to also be giving them a stimulant as an adjunct. This is instead of a drug.

Colin Keeley: Yes. Part of that is an artifact of the trials we ran. The team we worked with at UCLA wanted to use this device as monotherapy, because, as you know, stimulants can be a very effective treatment. They are a great treatment. But I did not want to give them to my daughter, who has ADHD.

Owen Muir: You know what? My kid was offered them too. And we have not done it yet either, for the same reason.

Colin Keeley: In order to get rid of that potential masking effect, we excluded people from the trials who were on medication.

Owen Muir: So no kids on meds in the study. These are medication-free children. What did you see in those trials?

Colin Keeley: There were two trials, an open-label trial of 24 subjects and a blinded study of 62. In both cases the primary endpoint was the ADHD-RS-IV scale. The DSM-5 came out and now we are calling it the ADHD-RS-5, but this was a few years ago. The ADHD-RS-IV is a clinician-administered scale and one of the gold-standard scales in the field for assessing the severity of ADHD. The children used the device for eight weeks in the open-label study and four weeks in the blinded study. We went to eight weeks because the open-label showed that over 90 percent of the effect was apparent by week four, so we thought it was unnecessary to keep going. Both trials showed a statistically significant improvement in the children who received the therapy. The other finding I really like, from the blinded study, is that at baseline and at four weeks all the children received an EEG. Among the children randomized to the treatment group, there was a significant increase in EEG power over the right prefrontal region. That corresponds with Dr. Cook’s PET findings. And as you know, there is a good amount of literature showing that at least a significant portion of the ADHD population has decreased right prefrontal cortex activity.

Owen Muir: Yeah.

Colin Keeley: So that is very interesting to me. One, I love anything biological I can point to, like the PET data, that says this thing is doing something to the brain. Two, there is the potential to use that EEG signal as a biomarker. That is something we are actively looking at now: how do we turn that EEG finding into a way to both predict and track treatment response over time.

Owen Muir: So it may be that for children who are likely to find this treatment helpful, EEG could give us a signature letting us know that is the case?

Colin Keeley: That would be the ideal. Everybody in psychiatry is looking for these kinds of biomarkers. There is obviously a lot of work to do to prove it is true, but that would be great.

Owen Muir: And if we found the way to tell, that matters, because every parent wants to know: is this going to work for my kid? For years the problem with ADHD, at least as I see it as a child psychiatrist, is that ADHD was almost synonymous with getting treated with a stimulant medication. Those are controlled substances. In people who do not have ADHD they are frequently abused, so people are wary of them, and they have adverse effects. Even though they are very effective, some of the most effective drugs in all of medicine, they still have adverse effects, and nobody wants to feel like they are poisoning their kid. So what I am hearing is that Monarch, which I am proud to have historically prescribed frequently with the gen-one device, and what I found in both kids and adults is that many of them had a really nice response, and when it worked well it worked great. I would love to know that in advance. And some of your science says there are ways to measure it in the brain, so we do not just need the opinion of the kid or the parent about whether it is working.

Colin Keeley: Yeah, we want to be able to.

Owen Muir: Move more and more toward something that is just endlessly safe. So as a monotherapy, with no serious adverse events, what risks are there?

Colin Keeley: This is not a regulatory conversation, and I would have to go through our instructions for use to give you the full list. But in my experience, the two main complaints I get are, first, headache. We are applying a small amount of electrical energy to people’s foreheads, and some people simply do not like the sensation. They say it is painful, or that over time it gives them a headache-type feeling they do not like. Generally, if they turn it down and give it a little time to get used to, that can be mitigated, but it is not for everybody.

Owen Muir: We actually found the same thing. At Neurolief, which has a trigeminal and occipital nerve stimulator for depression, we found that depressed patients turned it all the way up in our study, even though that was not the right answer. So we built a one-week ramp-up into the commercial product that does not let you turn it all the way up, because, bless our patients, they want to get better and they want to jam the number all the way up, and that is not necessarily the physiologically correct answer. It is a known problem, but it also speaks to how much patients want to get well. They will sometimes do things that seem sensible but are actually a little contrary to their physiology.

Colin Keeley: Agreed. Some people get a headache if they turn it up too much. And the other thing we do see is skin irritation, because it is an adhesive on the skin. We use hypoallergenic materials and have done everything we can to mitigate it, but some people get a reaction over time, a redness at the site of the patch. Generally, if they take a few days off and use a little over-the-counter steroid cream or lotion, that can be mitigated as well. But nothing works for everyone.

Owen Muir: But it is not, I had to take a controlled substance and ended up shorter because of it.

Colin Keeley: No, it is nothing like that. We do not see effects on appetite, or heart rate, or things like that.

Owen Muir: Right. There is no black box warning for sudden death.

Colin Keeley: No, certainly not.

Owen Muir: Tell me what makes the gen-two device different from the gen-one device.

Colin Keeley: In the age of the iPhone, people expect more from their electronics than the gen-one was offering. Therapeutically the devices are identical. They deliver the same waveform and the same electrical parameters. But the gen-one was a little clunky. It was more of a research-type system. You had to change the batteries and charge them manually. The screen was difficult to read, and it was hard to know where you were in your therapy session. So we integrated the battery, just like a cell phone, and it charges with USB-C. We added an OLED screen to the front and had a professional designer build the interface, so it is very clean and it is clear exactly what is happening. It is a significant upgrade in usability, and in how easy it is for patients to interact with the device.

Owen Muir: And this is a prescription device.

Colin Keeley: It is.

Owen Muir: So you need to see your doctor if you want one. How do doctors get in touch with NeuroSigma if they want to prescribe it?

Colin Keeley: The easiest way is our email. For physicians, that is medical.affairs@neurosigma.com, or orders@neurosigma.com if you have questions about the ordering process. We also have a helpline, though I do not have the number memorized.

Owen Muir: That is okay. I am sure they can get it if they email orders.

Colin Keeley: The website is far and away the best place to start. That is www.monarch-etns.com, and we have a section for both patients and healthcare providers.

Owen Muir: Let me summarize, and you tell me if I am getting it right. NeuroSigma’s new Monarch gen-two device is a treatment, as a monotherapy, for kids seven through twelve, that treats ADHD.

Colin Keeley: That is correct.

Owen Muir: Monotherapy means it is not a drug. It is a device instead of a drug, and it is safe and effective according to the FDA. The risks are things like headache, if you turn it up too high and maybe even if you do not, and skin irritation, because there is a sticky patch on your head. Right now the label says you wear it overnight, and you are looking at future studies on wearing it during the evening to see how much you actually need. And it is available now. People can get it.

Colin Keeley: Yep. It is a pretty easy process. Send in the prescription and we mail it directly to your home through a pharmacy we work with.

Owen Muir: So it goes through a pharmacy you work with. It is basically like filling a drug, except you are filling a device.

Colin Keeley: Correct.

Owen Muir: I am very excited, and I look forward to having more conversations, but I want my readers to know about it now. Anything else you want the audience to know? Because I am, frankly, obsessed with this device. It works really well, it solves a lot of problems stimulants do not solve, and it is great to have a meaningful and, in my opinion, even safer option.

Colin Keeley: I really appreciate it. I have learned a lot about neurodevelopmental disorders during this process, and I hope we can expand into other neurodevelopmental disorders as we progress. We thank you for your interest, and people should feel free to reach out if they would like to learn more.

Owen Muir: Can’t wait. Thank you so much.

Colin Keeley: Thank you, Owen. I really appreciate your time.

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Sponsors include:

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With a great update—the Tickets to the event are now FREE!!!

I'm working on some longer form writing.

I might get some articles done.

Today, for your amusement, I will share this podcast interview from back in the day, on the fantastic suicide-prevention podcast “Before You Kill Yourself” with Leo Flowers. We talk about bipolar disorder and staying curious.

As a reminder, I have a book—Inessential Pharmacology, on Amazon.

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Other classics from TFPs on bipolar disorder include the following:

And of course, an all time favorite from my readers:

Thanks for reading, listening, sharing, and subscribing.

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They exist to allow patients to taper off of antidepressant medication safely.

I’ve written about the lack of efficacy in these oral drugs before. For example, in my book Inessential Pharmacology. (Amazon affiliate link). I've got three other physical books already, two of which are poetry, the least commercial art form on earth. One is a therapy manual published by Springer Nature.

Mark’s book is the Maudsley Deprescribing Guides.

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MH: So, look, I'm originally from Australia. I grew up in Sydney. At the age of 17, I made a very ill-informed, immature decision to embark on a medical degree. I decided to add on a double degree. I earned a degree in philosophy of medicine and decided to add on a psychology degree. I've got an issue with degrees. I think, you know, four is good, two might be impressive, but six is pathology.

OM: I'm guessing you would advise against that now?

MH: I strongly advise against it. There are better addictions to have. Much cheaper. I advise you otherwise regarding both finance and time spent.

OM: The earlier you start the process of pursuing multiple degrees, the more likely it is you'll become addicted. (laugh)

MH: I'm a hardcore student. At some point, I had to tell people to block me from enrolling in another degree. I moved to London 15 years ago for a master's and a PhD in neuroscience and psychiatry. I was very interested in understanding the brain to make sense of depression and how antidepressants worked.

OM: Why London?

MH: In my early years, someone told me, “The best place to do psychiatry in the world was the Maudsley Hospital in London.” I'm a British citizen as well. My mother was born in Scotland because my grandparents escaped from the Holocaust.

Maudsley is a hospital that happens to be next door to the Institute of Psychiatry, the most prominent research institute for psychiatry in Europe. That's where I did my PhD, at the Institute next door.

I did a master's in neuroscience for a year, where we went around different labs, and then I chose a lab to complete my PhD. It was with a professor of biological psychiatry called Camino Pariante. I did it for about three years. I looked at the biology of depression. We used human brain cells in a dish, and we tried to simulate depression by adding stress hormones and inflammation and looked at the effect of antidepressants and whether they could reverse that process or not. This is an area of research that I now see as ridiculous.

OM: And when you say you '“now see it as ridiculous,” describe how you could have missed that at the time?

MH: You understand why people get rapidly beating heart and chest pain by understanding the physiology of the heart. That makes sense. There's an analog thought that we'll understand mental health conditions by understanding how the “brain works.” Understanding neurons, synapses, and neurotransmitters is the level at which to understand mental health conditions. I think that's the animating kind of theme of modern psychiatric research. I think that's ridiculous now. Mostly because I think it's premised on a category error. Because I believe that, essentially, people are miserable or anxious because of what happens to them in their lives, at least most of the time. Trying to understand that at the brain level is like trying to understand why a software program is broken down by looking at the hardware in the back of the computer. Yes, in one sense, all software issues exist in the hardware; that's true. Without the circuits, you can't have any software. But when software goes wrong— do you open up the circuit board and solder? That doesn’t make sense. There have been so few insights developed by looking at neuroscience to understand mental health conditions. However, there is a huge relationship between social circumstances and people's mental health symptoms. I spent years looking at nerve cells to understand human emotions. So, of course, my name is on several papers that came out of that lab. Most of them are null findings, I should say. I don't think anything of great help to any human being came out of that lab.

OM: What moment did you have the insight you're describing now that you felt biological science would not yield fruit?

MH: It was not until years later. I want to claim that I came to these insights through being clever, thoughtful, introspective, or anthropologically minded, but I'm not so clever. I came to become critical of the paradigm of biological psychiatry, not through any intellectual work, but because I almost died from the treatments that a psychiatrist gave me.

Well, it wasn't prescribed by a psychiatrist. I didn't see a psychiatrist until late in my career as a person taking psychiatric medications. When I was 21, I was a very miserable young man. If you've ever seen a Woody Allen film, I came from a family, a family like those films portrayed, I was very uncertain about life. I went to see a GP, I think what's called a primary care physician in America, and like one in two people, I was offered an antidepressant. It happened to be Lexapro.

The generic name is escitalopram, which is the most popular antidepressant in Australia these days. And they came onto the market a few years before I walked into my GP's office. I was given a starter pack from one of the drug companies. I took that for many years.

During medical school, during my training in psychiatry, and my Ph.D., I took this medicine. I guess there are two major effects it had on my life. Number one, I had a lot of health problems while I was on the medication. They were profound daytime tiredness and fatigue. Later, memory and concentration problems developed, and these increased over time.

As a younger man, I had a brilliant new photographic memory. As time went on, my memory and concentration got worse and worse until they became quite bad. It was quite pronounced and quite worrying, and it had a big effect on my ability to function well. It became quite embarrassing, forgetting things quite often. Most of the time, it was daytime fatigue.

A Brief Message from our “Live-Events Motion:” Join us at our next RAMHT event—opening night of Psych Congress, September 14th!

Sponsors include:

Definium Therapeutics

BrainsWay

Salma Health

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MDHub

Axsome

Universal Brain

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OM: was lexapro the only medicine you were taking at the time?

MH: Yeah, for many years, I took just Lexapro escitalopram.

OM: My, my level of envy to hear that statement! I have bipolar disorder. Polypharmacy has been my life — then, I developed an autoimmune condition thereafter. So if there was a thing to blame, you knew which one.

MH: Well, it started as the only one for the first 10 years, but it didn't end up as the only one I ended up on, on five different drugs.

OM: Oh God.

MH: In retrospect, it was a prescription cascade. What happened was I was very tired. I would fall asleep during class. Eventually, a professor said, “This is very strange. You keep falling asleep every in every lecture.”

He sent me to a doctor. I was diagnosed with narcolepsy, type two narcolepsy.

OM: You had an MSLT for that? [ed: this is a medicine abbreviation for “multiple sleep latency test,” the gold standard for the diagnosis of narcolepsy]

MH: I had several of them, um, and that was positive, and so I was given a diagnosis of narcolepsy, and because of that, I have prescribed stimulants of various forms over the years, Ritalin, modafinil, and essentially what happened over time drug side effects, which accumulated more drugs. So, because it made me anxious, different and more drugs were added. Because it made it hard to sleep, different sleeping tablets were added. So, at the height of my career as a psychiatric patient, or I guess you could call it a neurological patient also, I was on two antidepressants, mirtazapine, escitalopram, methylphenidate, and Zopaclone. The next one—and the last drug I was on—was gamma-hydroxybutyrate or Xyrem.

I started off on five drugs, I've come off four of those, and I'm down to the last little tiny, uh, bit of mirtazapine is the last drug that I'm on, I'm just a quarter of a milligram, so a little speck of a drug.

I guess in coming off those drugs, one of the main things? All those symptoms I experienced have resolved. Daytime fatigue, memory, and concentration issues. Although I'm not back to being the 20-year-old that I was— I certainly don’t have anything like the level of impairment I had on all these drugs. I was impaired to the degree that whilst I was on these drugs, I worked only part-time because I was so fatigued.

OM: Oh my God.

MH: I've returned to full-time work. There was a point at which I was so impaired that I thought it was unethical to keep practicing as a doctor because I would write down everything that was said to me. And if I lost my piece of paper, I'd forget things. If someone asked me, “How was that patient you saw two days ago?”

I could barely remember who they were talking about. I reached the point where I thought it was unethical to keep practicing like this, and I could still take medical retirement. It was quite impactful on my life. I am getting back my ability to think straight. Being energetic during the day has been an incredible gift to me. I feel like I've been given a second chance at life. So that's the first aspect. The second aspect is the bit that almost killed me.

MH: The bit that almost killed me was coming off the drugs initially.

OM: One of them is Xyrem, which can absolutely kill you. [ed: abrupt withdrawal from Xyrem (generic: Sodium Oxybate) can lead to seizures and death]

MH: It wasn’t the Xyrem! It was coming off Lexapro (escitalopram).

OM: Wow.

MH: That was pretty close to not surviving.

OM: Oh, my gosh.

MH: Towards the end of my PhD, I came across a paper talking about withdrawal effects from antidepressants. I found that very startling because I hadn’t encountered talk about withdrawal effects from antidepressants in either medical school or my training.

One, drugs that cause withdrawal effects also cause tolerance because they’re the flip side of the same coin. So I thought, I’ve now been on a drug for 13 years at that point. How could it still be having any beneficial effect? Number one and number two drugs that cause withdrawal effects are generally not all that good for you.

You know, benzodiazepines, oxycontin. These are not drugs that you want to be on long-term. And so I found that jarring. It had been on my list. Maybe to try coming off my drug and reading that paper knocked it up to the top of my list. And so what I did was. I, you know, I’m a very nerdy human being.

I went and read all the academic literature about how to come off antidepressants. And a lot of it was written by people I was working with. I was working with professors at Oxford and Cambridge. They all said the same thing. Withdrawal effects from antidepressants are mild and last a week or two.

And you can avoid them by coming off over about four weeks. Well, that sounds reassuring. And then, because I’m a millennial—a geriatric millennial— I went and read online. I went to Google:

MH: I encountered a quite different narrative. People online said it was incredibly hard and took them months or years. Sometimes, I read that it could create much worse states. Even worse than the issues that people went on the drugs for. I’m an “institutionalized person.” I’ve got six degrees. I spend a lot of time listening to professors. I didn’t know whose opinion to take! I decided to split the difference and to come off over four months, not four weeks, but not four years. I did that by getting a liquid version of the drug and using a micropipette from my biological psychiatry laboratory. So, I used the equipment I was familiar with from the lab.

OM: Is there an irony there?

MH: Yes. I was shuffling equipment out of the lab at night to measure small doses at home. I turned into a kind of Walter White character! I halved my dose every month for about four months. I was on 20 milligrams, I think, to start with or 15 milligrams, and by then, I was at one milligram.

I got down to one milligram, and my life basically imploded. I had trouble sleeping, and every morning, I would wake up in full-blown panic, even terror. But I had an experience in my life before. It was animal-level terror, like wild animals chasing me on the edge of a cliff.

I hadn’t experienced before heart beating, palm sweaty, and that would last for about 10 hours of the day. By nighttime, I’d get a little bit of relief. I took up running, which would be a bit of relief. I ran so much my feet. I listened to hundreds, if not thousands, of repeats of body scan meditations.

It went on week after week after week. At some point in there, I thought, I’m not sure I can keep living like this. This is so unpleasant day after day. I was dizzy. Things around me appeared unreal. There wasn’t a single second where I thought this was me returning. At 21, I was a miserable human being.

I was pessimistic. I was ruminatory. I’d never had a panic attack in my life….and here I was. I’d never had trouble sleeping. I’d never been thinking of ending my life. What I experienced at age 21? That was a 3/10 existential-level dilemma. What I lived through when I stopped the drugs? That was 9.75 out of 10. Eventually, I thought I couldn’t keep going like this.

I went back on my drug. I returned to 20 milligrams, even higher than I’ve been on before.

OM: Oh, wow. That says a lot!

MH: I realized I was now on this drug, not because it was helpful, but because I couldn’t stop it. I was now on this drug. I met every definition of being physically dependent on this drug.

OM: I’ve been through a similar experience with pramipexole. As I wrote previously, it similarly almost killed me— Dopamine agonist withdrawal syndrome! I was following the taper my doctor prescribed. I went down from four milligrams, which is an insane dose, I later learned, down to 0.5 to 0.25mg. A month into the 0.25mg, I was thinking of pouring gasoline on myself:

The image of pouring gasoline over oneself and lighting a match is not a pleasant one. It’s not pleasant even when you’re thinking about someone else doing it, who is invariably a monk. Monks are in virtually all of the pictures that exist of this activity, because the most viewed image of this is on Rage of The Machine’s breakthrough album. Monks are different from regular people. Monks are not you or me on average. You don’t go to work wearing a monk outfits unless you’re a monk. Monks are conceptually far enough from early-40s, tubby, balding, white physicians as to allow for a sort of emotional and cognitive distance.

Your story, Mark, is very relatable. I also, it turns out, have something close to narcolepsy. Still, once you realize that you’re chasing the dragon, as it were, with these medicines that you can’t stop— is there the fear that, like traveling, going anywhere, is doing anything? “What if my supply of the medicine were to run out? Did you know that you were bound?

MH: Some of those thoughts did cross my mind. I think I’d had them before because I’d been on the drug for over ten years. I thought I’d always got to have the drug. I guess it became more clear to me. What I didn’t realize? I was walking on a tight rope, three meters above the ground, and if I tripped, I would end up falling only three meters.

It did make me think about flying and having a supply of the drug. But I guess to me, the biggest dilemma was something slightly different, which was, as I was reading about people’s experience on these drugs, I came across a lot of people who said exactly what I said. After starting these drugs, I fell asleep all the time during the day. I was diagnosed with narcolepsy.

And so I crystallized my thoughts, thinking maybe these drugs are what’s causing my fatigue. I thought I was caught between a rock and a hard place here. I’ve been fatigued, which has caused incredible trouble in my life. It affected relationships and work. So, I had to accept this fatigue as I returned to those drugs that caused it. I thought being on this drug was causing me so much trouble in my life. It’s hard to express the way it affects relationships. I miss events. I fall asleep. I arranged my life around naps; it’s entirely consuming, and coming off this drug almost killed me.

Now, I’m back on a drug that’s causing me all these health problems. Coming off, too, was incredibly dangerous. So, I felt trapped. I was! I’m trapped on a drug. It’s causing me a lot of different, terrible side effects. And it looks like I can’t come off it because it’s too dangerous. So I felt I have no moves left on the chessboard.

OM: That’s not the end of the story. Which is nice to know. Knowing the end of the story is always calming! People make a joke about playing 3D chess, and my response to that is that there are 10 ^ 40 moves available in chess. That’s what’s called the Shannon number. If you go to all the possible moves, including illegal moves in chess, you get 10^123. On my math nerd soapbox, 3D chess requires more moves than there are atoms in the entire universe to calculate the change in those moves. There are between 10⁷⁸ to 10⁸² atoms in the observable universe. That’s not plausible. There are more than enough combinations on the regular chessboard. So here—running out of moves for being stuck on a drug— was a moment of…in the hero’s journey, we’d call this “tests, allies, and enemies” or something like that?

You’re also a psychiatrist and psychiatric researcher who has these tools at his disposal to do your job. What are you doing? That’s what I’m thinking anyway.

MH: That’s good. I appreciate you raising the stakes on this and making it more dramatic than it might be. So I’ll tell you how I solved that issue. I was so shaken by what had happened coming off the drugs. I quit my job in London and moved back to my parent’s house in Sydney. I was an ostensibly grown adult human being in my thirties. But I ended up basically in a kind of crumpled mess on my parents’ floor. I, having moved out of the house ten years before, was so relieved when the symptoms went away after a few weeks back on a higher dose I put it to the back of my mind for a while.

I was back in Sydney, I was working as a psychiatry trainee, and I had this sort of thought in the back of my mind: these drugs are not quite what I had been taught they were. But I was just back in whatever role of life and trying to keep up with work, so it didn’t occur to me—I was living relief.

Because I was back with my family, I had access to my parent’s private health insurance, which I didn’t have in London. I ended up seeing more doctors. I was still quite confused. And I had doctors saying to me, you’ve got terrible narcolepsy. You need more different medications.

I still had terrible fatigue, and I wasn’t confident at that point the drugs caused it. I had an inkling, but I wasn’t certain. I followed their advice. I was given more drugs and more stimulants, which led to more anxiety, which led to more antidepressants. They tried these newer drugs, xyrem, and sleeping tablets. And I ended up on five drugs back in Sydney now a few years. And I didn’t see it, but in retrospect, it’s quite clear the more drugs I was on, the less able I was to function. I found work hard, memory, concentration. At some point, I decided to take a break from work. I went, and I took eight days of leave.

This is where it gets a little bit cliched. It turns into a kind of eat, pray, love. I went to do a yoga meditation retreat in Thailand. I couldn’t be more of a bourgeoisie cliche if I tried. I did a lot of walking meditation there in a Thai jungle Buddhist temple.

And I thought, why am I on all these drugs? Have they improved my life? I decided I would try coming off them to see what’s underneath. I solved that chess dilemma by following people who’d done it before me. So, it wasn’t being trained as a psychiatrist. It wasn’t psychiatric research. Recall there are 10^40 legal moves, but you said many more illegal moves in chess? I made one such move, not according to the rules I knew. I turned to peers on the internet.

They said you do it much more slowly than a few months, sometimes more than a year or even longer. You followed a specific pattern, reducing your most recent dose by 10 percent every month.

So it gets smaller and smaller. You can reduce by 10 milligrams at a hundred milligrams, but when you get down to 10 milligrams, you reduce by one milligram. There were all these people, actually tens of thousands of people, on these peer support sites saying when they followed this way of coming off antidepressants, it was easier.

It wasn’t a walk in the park, but it was nothing like coming off over a few weeks, as most doctors recommend. I didn’t have to work out anything myself. I had all these people saying, “This is what works.“ And the reason why I trusted them was that I tried the traditional way of coming off over a few weeks. I’d even gone slower. And it almost died. I knew who the experts were now. They weren’t my professors at my university. There were these people online who, through trial and error, mother being the necessity, whatever necessity being the mother of invention being the mother of necessity, whatever it is, had worked out how to do it.

OM: The plural of anecdote is not data unless so many anecdotes exist?

MH: It depends on what you look at, what data is, and what anecdotes are. The data that my professors were basing their opinions on was that after eight weeks of exposure to antidepressants, most people have mild symptoms that last for a week or two.

OM: That’s true. Most people can come off over four weeks.

MH: That’s also true! Of course, at that point, I’d been on the drug for 13 years.

OM: So, they based it on the wrong sample.

MH: Exactly. It’s a bit like crashing a car into a wall at 5km an hour and saying it’s safe and extrapolating that to people driving around 80km an hour. In other words, the data that existed was not very good. In that context, looking at the hierarchy of evidence, 10,000 people talking about not being able to come off in one way and coming off in another way was the best data around. So, I followed what these people recommended on these websites.

And I thought, what’s the harm? How can going off more slowly be wrong? I’m guessing the answer is that the experts were basing their opinions on the incorrect data. They had a very select data set of people who’d been on for brief periods.

OM: Why would pharma study people who were on for 13 years?

MH: They’re just not in the available data. And the people online were a much larger group.

OM: They had a different biology.

MH: I think there are two important points to make here. First, drug companies are required to do 6—to 12-week studies to get their drugs approved by the FDA. That’s why they do a 12-week study. And about, there’s probably about a thousand studies of antidepressants done. 97 percent of them were done by drug companies. And 97 percent of them go for no more than 12 weeks. And there are no studies on long-term people who have stopped long-term antidepressants.

For example, the guidelines from the American Psychiatric Association today tell people how to stop antidepressants? They say you can stop over several weeks. And that is based on people who’ve been on the drugs for eight weeks. So, as you just said, the current evidence-based guidelines are only appropriate for short-term users.

Whereas in America, we know that half of people have used these drugs for five years or longer. And more and more people have been using them for ten years or longer. And we know that the longer you’re on these drugs, the harder they are to stop.

OM: Yeah!

MH: Exactly—it’s not that the people online have different biology; it’s that they have been using drugs for a long time. Much longer than the studies. There are 46 million people on antidepressants in America. Twenty-three million of them have used it for more than five years. It’s reaching 10 million plus, and I have been on it for over ten years.

OM: There’s an insight that you recognize—which was that being on a drug for 10 years is not the same as being on a drug for 8 weeks.

MH: That’s right. And data backs it up. Now, there’s research that shows the longer you’re on these drugs, the greater the chance of withdrawal effects and the greater the chance that they’re severe. Which is obvious, of course, the longer you’re on a drug, the more you adapt to it, the harder it is to stop it.

So, no, there’s no rocket science there. What happened then to me was I took this approach. I took 10 percent a month approximately, and two major things happened. Number one, it was a lot easier to do that than to come off the medication more rapidly so I could tolerate the process. It wasn’t horrible. Many of my symptoms also started to resolve as I came down off my drugs.

My tiredness improved, and my memory and concentration improved. That was the start of me realizing, very clearly, that it was these drugs doing it. That gave me a lot of hope and push to keep going. The second thing that I did was think this was utterly unbelievable.

I’ve got a PhD—in antidepressants!— from an institute that, while I was doing my PhD, passed Harvard as the most cited institute in the world. I’m trying to be a psychiatrist, but I’m getting more helpful advice from online peer support forums run by retired software engineers and homemakers. How is this happening?

So, I wrote an academic article combining the things I’d learned from this website with some academic research that reflected what was going on. I published that paper in Lancet Psychiatry. Over the last five years, that paper and the work around it have led to quite large changes in the guidelines in the UK [ed: NICE guidelines] on how to stop antidepressants.

It ended up being several papers. Number one was theoretical work, and number two was an observational study. So, the theoretical work is that we looked at the neuroimaging of antidepressants.

OM: Similar to Kapur’s work on antipsychotics?

MH: It’s a Harvard guy, a guy called Jeffrey Mayer, who did in 2004; he scanned a whole lot of people on different doses of standard antidepressants. Look at how big the effect was on people’s brains and what he found. Can I show you an image?

So, this is PET imaging of people on different doses of citalopram, a widespread medicine in America. It’s looking at the drug’s effect on the brain, which is inhibition of the serotonin transporter.

The key point is that the relationship between dose and effect is not a straight line. So, doubling from 20 milligrams to 40 milligrams doesn’t double the effect on the brain. Huh. This is because of the law of mass action. When there’s not much drug in the brain, all the receptors are unoccupied and “open for business.”

And so every milligram of drug has a significant effect, like the game of musical chairs at the beginning. It’s very easy to find a chair by the time more and more of the drug is in the system; more and more receptors are occupied. So, every extra milligram of the drug has less and less effect. And that’s why you get this sort of law of diminishing returns.

And so one of the consequences of this is very tiny doses of drug, like two milligrams, Which people would laugh at and say is a homeopathic dose has about half the effect of 20 or 60 milligrams. So tiny doses like 2 milligrams have much bigger effects than you would think. You can use this relationship to try to understand what happens when people follow the kind of advice that most doctors give.

So, most doctors would recommend coming off 20 milligrams of citalopram by recommending halving the dose. And then half the dose again before stopping it is, but what your data shows is that no, essentially, stopping at five milligrams…

OM: you still have the vast majority of the effect of the drug to be rug-pulled…

MH: Exactly. You’ve got it. So you can imagine walking down. If this was a path, it starts as a garden path. You can walk very easily. It turns into a steep hill, and then it turns into a cliff.

OM: But there’s a bias here because every doctor recommending to go down from 10 to 15 is correct. They get to feel better about their role as doctors again when someone goes from 15 to 10. And from 10 to 5, things go fine. So they have this smug sense that things are going to go fine.

MH: Yes, yes, exactly. People are a bit reassured because the earlier reductions are easy. This is going fine. Yes, my doctor has got things under control!

OM: But on both sides, it’s wrong! The doctors are convincing themselves they’re doing a good job, and their patients are feeling like the doctors are doing the right thing. And there’s no data to suggest to either party that it could be a disaster…until the cliff.

MH: Exactly. So what happens at the cliff is that people jump off. They can end up in a state of terror like I was. And because most doctors don’t understand his relationship, they think they must need the drug; maybe the last five milligrams are the most important.

OM: Your depression has come back!

MH: Yes, exactly. So, they tend to misdiagnose relapse of depression or anxiety. I’m sure if I’d walked into any doctor’s office, When I was panicked, terror stricken, I’m sure anyone would have said to me, you’ve relapsed clearly, your condition’s gotten worse.

OM: I have a question for you: How long after a discontinuation or taper event can this kind of experience of horror and dread appear?

MH: It’s a fascinating question because the textbooks say it should take three to five half-lives, which is about three to five days after most drugs.

OM: Those are textbooks about drugs. Not about neurons responding to what happens later, there’s counter regulatory effects that the drugs have been doing for years.

MH: Perfect marks! Precisely. So, a study looked at the average onset of withdrawal effects in a cohort of patients. It found that it was about four weeks with a standard deviation of 13 weeks; in other words, it’s enormous. It’s a large variation, but what it’s telling you is that some people experience withdrawal effects one, two, or three months after stopping their drugs. And there are two explanations for why that might be. Number one is “the mousetrap explanation,” which is that “you drop the ball. It hits the stick that presses the steps that do the whatever.”

OM: Rube Goldberg!

MH: It takes a while for things to unravel! Number two is based on a fascinating study that posits, “It takes a lot longer for the drugs to leave the central compartment than we think.”

For example, after a couple of weeks off a medicine, you can still see it affecting specific transporters inside the brain. In other words, the brain elimination half-life is longer than the plasma elimination half-life. Between those two explanations is probably why you can have withdrawal effects that come on weeks or even sometimes months after stopping the medicine.

OM: There isn’t a “liver in the brain” to metabolize the drug. Most drug metabolism takes place in the liver for compounds in the blood, of course.

MH: Oh, you are asking if the drug must go into the blood across the blood-brain barrier and hit the liver? But there’s another interesting study that shows that the elimination half-life in the brain is slower.

OM: And that fits with data from Kapur’s lab at UCL, where he showed with PET scan data that aripiprazole has this tremendously long half-life, and its dopamine receptor occupancy one week later is the same as on day one.

MH: That drug has a long half-life.

OM: But it also hangs out in the brain for a long time. And so does its active metabolite and blah, blah, blah, blah, blah. So, there are plenty of reasons why things could hang around longer. The drugs— if the unwinding of the effects is longer? It messes with the human ability to make a causal inference.

MH: You can imagine the doctors reading the textbooks. It says mild and brief symptoms come on two days afterward. Someone’s in their office a month later.

OM: They look like death. They’re sick. And it doesn’t match the description in the textbook. So they think it can’t be withdrawn.

MH: It must be terrible mental illness, relapse, something else. You can see where the trouble comes from! They are guided by short-term studies that underestimate the withdrawal effects, which cause havoc in clinical practice! Well, this means that doctors are reading books that are not accurate for their patients. That’s huge trouble! We now have hundreds of thousands of people who have left their doctors and gone to online forums, just like me, because they find those forums more accurate and helpful than their doctors.

OM: Some people do have a mental illness—whatever that means and who are sick and could relapse.

MH: That exists. However, I want to problematize it a little bit. The vast majority of people who are prescribed antidepressants are prescribed by a GP or primary care physician; they’ve never seen a psychiatrist.

The vast majority of people who are prescribed antidepressants have mild to moderate conditions. The vast majority of people who have mild to moderate conditions see a GP or a primary care physician in the context of a major stressor: job loss, divorce, or physical illness.

OM: It’s hard to have a relapse of a specific divorce.

MH: In other words, it’s hard to have a relapse of a particular stressor in your life. Most people who are prescribed antidepressants do not have severe recurrent disorders. They have contextual stresses, which are in the past.

So, the idea of relapse, which is so prominent in doctors’ minds, isn’t often accurate, on average—the majority of starts on medicine are based on acute and non-recurring stressors.

OM: Essentially, this is my same argument about dubious “bipolar disorder.” If you treat everyone’s “bipolar disorder” with Seroquel, it works for their “mania” 100 percent of the time—because they never had the underlying disorder.

MH: Yes. Doctors get to convince themselves they did a great job of preventing the relapse of mania in someone who doesn’t have bipolar disorder.

OM: You argue that most people who are coming for help would be best served by someone helpful, listening, and supporting them psychosocially.

MH: I’m making two points. Number one, in most doctors’ minds, relapse is the horse, and withdrawal is the zebra. I think the data is clear.

OM: The overwhelming majority of people have been prescribed these medicines for mild problems that are in their lives?

MH: That the horse is withdrawal and relapses is the zebra for most people, some people, there’s some, there’s people out there with very severe conditions, but that’s not most people and do exactly what you’re saying.

The NICE guidelines in the UK, which evaluate cost-effectiveness, found that the most cost-effective treatment for even severe depression was problem-solving therapy:

That means you tell somebody what your three major problems are. What’s the first step to take for each one? And report back in two weeks on progress or barriers encountered. That’s more effective, and that’s more cost-effective than antidepressants. It’s more even cost-effective than various forms of psychotherapies.

I think that gets to the heart of the issue: people. It’s the things going on in their lives that tend to explain why people are miserable and anxious, and there are lots of ways to help them with that, of which I think only one is an antidepressant. And I believe that the way that antidepressants generally work is they numb people’s emotions.

I don’t know how much there are all these kinds of descriptions of biological effects and neurogenesis and inflammation that I was very Taken by, but I think when you ask most people on antidepressants, they say they feel emotionally restricted or numbed. And that’s why people can feel better in the short term, which is a bit different from fixing their problems.

OM: It’s fascinating that you’ve landed on the opposite end of the spectrum as I have in my career as a physician. I focus on very high-acuity individuals but have come to similar conclusions about the utility of these drugs.

In summary, if I am getting this right, in the world of primary care—where, on average, patients don’t have a severe chronic psychiatric problem—these drugs are causing one. In the world of high acuity problems, where you do have a severe problem, the drugs aren’t solving those. Riffing on what Dan Karlin once said to me, we perfected the algorithms to make these compounds as safe as water, at least initially. We have a generation of agents with the potency of water, but similar to withdrawal from water, that can be fatal, too.

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You can find my books (amazon affiliate links):

Inessential Pharmacology.

The Hellthread: Collected Poems

Why We Skeet: Further Collected Poems

Adolescent Suicide and Self-Injury: Mentalizing Theory and Treatment

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Look what happened to Srinivas Rao at AtaiBeckley: he joins us live on stage, plus one little academic article by my coauthors and I, and boom!

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This story is about a pair of winners—a nurse and a patient. I was simply an observer.

By the time I passed through the locked door between the hospital proper and the children's comprehensive psychiatric emergency program, there were already upwards of 40 people standing around.  Doctors, nurses, security guards.  I counted later, and it was actually 38.  Your brain remembers these things wrong, reliably.

The security guards looked particularly unsettled.  There were four of them. At Bellevue, the guards are all hospital police.  So they’re dressed like police officers, they stand like police officers, and kids respond to them like they’re police officers.  None of the names you will read are real.  Details have been changed for privacy.

“Nooooooooooo!” The shriek from within room one hurt my ears, and I was 2 locked doors away.  It has a combination of anguish and adolescent tonal instability that is both heartbreaking and ear rending.  

I moved quickly, and gave my key a quick twist to the right, and then another jerk, because the door had a sticky handle.  

I didn’t open it more than strictly necessary, and essentially slid myself inside, pulling it closed behind me.

The click.  It was satisfying.  Now whatever happens happens— but the door at least isn’t open because of me.  My control of the situation, thus, was exhausted. I tried to simply be.  It only worked so well.

The boy was tall, somewhere between 14 and 16, and the kind of slender body habitus meant that, to my eye, he hadn’t been in the system very long. Nobody had given this kid years of antipsychotics, yet, with the associated weight gain.  He could pass for a private school kid.  He had straight hair.  It was unkempt, and puberty plus terror or rage made sure I could smell how much he was sweating.

I turned my head about 15° to the right, and I saw the Director of nursing.  He was a short man, and I say that as a short man.  

The room in which this young person was pacing, relentlessly, back-and-forth, was spartan.  If bright white got sick to its stomach, that would be the wall color.  There was a window that had an extremely fine mesh metallurgical cover that once would have been called a grate. This safety device had clearly been clawed at by prior frantic children. 

The wooden bed frame was bolted to the floor, there was a thin foam mattress on it, but didn’t have any sheets at this time, and they were two straps, made of red nylon, one towards the foot, and one 3/4 of the way towards the head.  The slight scent of chlorhexadine used to scrub down the mattress when the ER ran out of ammonia because of a budgetary crisis presented itself, tucked under the sweat.  There was a pillow.  That’s all that was in the room.  Bullshit excuse for a window.  Extra long twin bed. Bare mattress.  The nylon straps had what we’re supposed to look like not very menacing buckles.

This was the upgrade, probably mandated by the joint commission of endlessly modernized horrors, for the four-point leather restraints that used to be standard at the beginning of my training.  But nobody here was in any way confused about the intent of the bed, or the straps upon it.  They were designed to take the arms and legs of that child, pacing in that room, there, who looks terrified, frantic, anxious, and was screaming the word, no, and give him no choice but to lay uncomfortably still.

And what turned out to be 38 people were crowded out in the hall, watching this robust young person, smelling this robust young person, fearing for this robust young person, fearing for themselves, as a child screamed, over and over again.  

“Don’t fucking touch me. Don’t you fucking touch me. Don’t you fucking touch me. No. No. No. No”

If a metronome had post traumatic stress disorder, and a history of psychotic mania, it would be this kid. 

I felt a hand on my shoulder.  The Director of nursing move closer to me, and, without taking his eyes off the young person, said, clearly and quietly in my ear: “ you’re the child psychiatrist on call?”

“Yes.” 

“Good.  You’ll do great.  The nurses already have pulled up a PRN.  I don’t think he’s gonna need it. Let me go in there first.”

Juan, without waiting for a reply, because frankly we worked together enough to understand that I knew my place, smoothly walked from the hallway, pressed down the door handle, that only pressed down for safety reasons, opened the door to the child’s room, and entered.  He stood, with the door open, and his feet, angled at 45° to the kiddo.  This is the most non-threatening angle.  His position was breathtakingly in keeping with all training videos, but his stance said more than just precision.  One knee bent, slightly.  Contra-posto—Michelangelos, David, if he was a nursing administrator and 20 pounds overweight from all the overnights.

I was a first year fellow at the Nyu/Bellevue school of medicine child psychiatry fellowship program.   Managing psychiatric emergencies in the middle of the night has been my job for some time, because we do an ungodly amount of emergency psychiatry notations in the name of education.  Most of the sickest kids in New York, come through the space, and we have tried to reduce the use of restraint and seclusion, physical or chemical for years now. There had been news stories about how often children got what both they and the press colloquially referred to as “booty juice”— injectable Thorazine to calm them down, in the hopes of right away.

“Hi, I’m Juan.  I’m a nurse here.  I’m actually the director of all the nurses for kids here.  What’s your name?”

“(Mumble)”

“It’s nice to meet you.”

“Don’t let any of those people fucking touch me”

“Oh, that’s good news, we’re on the same page about that.”

“What?”

“Well, I heard you were really upset, and people are concerned about your safety, so a lot of people show up to make sure that nobody gets hurt, but that can be really scary. If you don’t know, that’s what’s happening.”

“It doesn’t fucking look like that”

“It doesn’t look like that. Not at all.”

“Well?”

“I have a better idea, if you want to hear it?”

“Sure” the kids said. Softening, a little bit.

“So, a restraint has been ordered. And I’m a nurse, so I don’t get to say if it happens or not.  But what the order doesn’t say is who does that restraint.  A restraint is when you lie down in that bed, and the straps, go on your legs, and then go on your arms.  But the order doesn’t say who puts them on.”

“Don’t fucking touch me”

“That is kind of my point, the order doesn’t say who has to put them on, and it doesn’t say how long they have to be on.”

“A little weird”

“Kind of a loophole…right?”

“Maybe” the young man said, suspiciously.

“Do you wanna hear my idea?”

“Sure” said the boy, more firm now, his eyes a little bit wider, ready to bolt.

“Well, why don’t you just put yourself in?  And then tell me when you’re ready to get out.  And then we’ll let you out.  You only stay in the restraints as long as you need to, for you, and then we did with the order said.  Then we can get on with figuring out how to actually help you.”

“Seriously?”

“Seriously.  That follows all the rules, you get to choose, nobody has to touch you, and we get this thing over with, because I’d rather just talk— bet you would too?”

“Ok…”

I don’t remember the words that were said next between the two of them.  I remember, he lowered himself down, gingery, and Juan showed him how the straps and buckles worked. It was like he was instructing another nurse.  The kid took it in, breathed along, now calm, and focused on the task at hand.  First he put in his left leg, and fumbled a little bit with the red strap.  By contrast, the right leg was in one smooth motion, and his left arm, even more quickly. He even left just the right amount of room, from what I can tell, for New York City safety standards around these things.

“I have a question” young man asked.

“Yep?” Respond Juan.

“you know how to say that thing about not touching me? I need to take it back.  I need your help with this last buckle.”

“Good point” said Juan.  He gently placed the buckle around the child’s wrist, pulled it, not too tight. 

“So I can just come out anytime I want?”  Asked the young man.

“Yes, anytime you’re ready”

“Give me a minute or two. I’m not ready yet”

“I’m on standby”

One minute and 37 seconds elapsed according to the clock on the wall.  The officers had already moved themselves to the back of the room, towards the door, the nurses were no longer in a defensive posture.  

“How about now?”

Juan reach down, and undid the strap he had placed.  

“The rest are all you” he said to the young man.  

“Thanks, I appreciate it.”

Documented in my note that night was a total time of one minute and 37 seconds, and I checked an electronic box to indicate that no PRN medication was administered intramuscularly.  This was documented again, in a paper note, which will be required to also keep in the chart for compliance with the office of mental health.  My signature on that form ended up being the only reason I needed to physically be there that night.  

The state standard for the duration of that physical restraint was four hours— before a licensed doctor had to check, legally, for the first time, on how it was going.  And then once every four hours thereafter, till it was concluded.

Juan had signed the leave forms for every nurse who was put out on disability that year after being assaulted. The pediatric psych floors had the highest rate of workplace violence against nurses that year.  37 other people could have taken the lead and kept Juan perfectly safe.  Including me.  The psychological safety of the person who would have to remember being restrained by a hallway full of adults isn’t recorded past the time on the compliance form. 

This is the story that comes to my mind when anyone asks me about moral leadership in health care.  Leaders demonstrate mastery and compassion not by avoiding risk to themselves.  They act in ways that are unforgettable, so they don’t need to teach skills a thousand times—they need to show one, do one, and you can’t forget the lesson.  Ever.

—Owen Scott Muir, M.D.

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But have I been measuring the brain with EEG regularly? Well, no, again! I’ve been content with my fancy fMRI scans alone, for SAINT, and giant brain healing magnets at set frequencies, like deep TMS with SWIFT.

There are even videos of me talking about TMS, like this one below, with friends like Colleen Hanlon from BrainsWay, and heroic patients who chose to speak publicly, too.

But one thing I haven’t routinely done is measure the brain itself as part of clinical care, as companies like Firefly Neuroscience are making possible. That may need to change, is the outcome in my personal brain as a result of this interview. I speak, at length, with Dave Decaprio, their president and COO.

The EVOKE system provides multimodal analysis of brain function, including Quantitative EEG and Event-Related Potentials. From the Firefly website:

At Firefly Neuroscience, our technology is built to measure and interpret brain function in a clinically meaningful way. The Evoke™ system combines quantitative EEG (qEEG) and event-related potentials (ERP) to capture both baseline brain activity and cognitive response during structured tasks.

This data is analyzed against a proprietary normative database of over 191,000 EEG and ERP sessions, allowing clinicians to evaluate patterns relative to age-matched expectations and track changes over time. The result is a structured, interpretable view of brain function that can be used alongside clinical evaluation to support earlier insight, more informed treatment decisions, and a clearer understanding of patient progress.

I haven’t used it in clinical practice yet, but Dave makes a compelling case, and at this point I think it’s only a matter of time. Brain Medicine, as an emerging specialty, brings change. That change needs to be measured. EEG might be one such tool.

I hope you enjoy today’s podcast! And thanks to , , along with Dave, for their guest spots.

—Owen

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Announcements:

• You can Join The Frontier Psychiatrists LIVE at Psych Congress 2026. Get your tickets now!

• You can buy a copy of my IRL in print book on Amazon, Inessential Pharmacology. It’s got a lot of good reviews, and one “one star” review, which, in the spirit of transparency, I will excerpt for you:

The author has taken a collection of drug leaflets from pharmaceutical companies and woven them together with underwhelming lackluster commentary and memes. He intended to create an engaging reading experience, however, this aim should have been clearly stated, should have been made explicitly clear in the book description. He wanted to have fun writing it and wanted readers to have fun reading it. Now, having missed the return window, I find myself stuck with a book that feels more tedious than enjoyable.

Don’t miss the return window if you hate my work! Good advice for us all.

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Given the happenings, which are positively Shakespearean in character, I’m going to begin this article with a a key definition:

• Narcissism is a personality trait. It’s defined thusly:

“Personality qualities include thinking very highly of oneself, needing admiration, believing others are inferior, and lacking empathy for others.”

This is distinguishable from plain old grandiosity, where someone believes themself to be great or important, in that a key feature of narcissism is the belief that one is better than others and the entitled to admiration because of that special status.

The thing about empathy is that having too little of it makes it really hard to imagine the minds of others in a way that’s productive for you. Too much narcissism, with too little empathy, can take something that’s a personality trait, and have it tip over into the realm of a disorder.

People with narcissistic personality disorder are impaired. That’s what makes it a disorder. It causes impairments in their life.

Usually, this is hard to explain to people. Today it’s not. A narcissistic impairment looks a lot like somebody trying so hard to one up a teenage girl that they might have alerted authorities to their location when there are outstanding warrants for their arrest.

Our antihero is a man. He’s pretty clear on that.

His name is Andrew Tate. I can’t make a diagnosis for a man I haven’t met. I can talk about presumptive diagnoses for Shakespeare characters and make comparisons.

I know, I know. I was expecting Macbeth to be older also. So, the young Thane of Tate1, he’s a world champion. And he’s here to help us escape the Matrix. Because, you know, nothing says great financial advice like a guy who’s been kicked in the head so many times he lists “Media Personality” as his job in a Twitter profile. But wait, there’s more:

Apparently, the red pill is available to all of us. And like Morpheus before him, he’s here to help us escape from the matrix. He’s got the secrets to wealth creation. He’s so good at wealth creation that he doesn’t seem particularly concerned with the fuel costs for his car. And if there’s one thing I know about wealthy people, it’s that they’re not concerned about cash outlay in the slightest. They really don’t mind the store when it comes to expenses. They also love investing in a rapidly depreciating assets. In the case of Mr. Tate, he’s happy to tell a teenager flaming him on the Internet about his extremely fuel inefficient car collection:

Just as in the plays of William Shakespeare, tragedy is timeless, and the themes repeat throughout history:

Shakespeare wrote the majority of his tragedies under the rule of James I, and their darker contents may reflect the general mood of the country following the death of Elizabeth I, as well as James' theatrical preferences.[1] Shakespeare, as was customary for other playwrights in his day, used history, other plays, and non-dramatic literature as sources for his plays. In Elizabethan England there were no copyright or protections against plagiarism, so characters, plots, and even whole phrases of poetry were considered common property.

The tragic character of Andrew Tate, in the grand tradition of William Shakespeare, may fit better in the mold of “a problem play”—in that like some of Shakespeare’s finer works, it’s not strictly speaking only a tragedy or comedy, it’s definitely both. Much like the quoted, tweet format on Twitter, even back in Shakespeare’s day, entire phrases of poetry were considered common property. Just like Andrew Tate’s tweets have been totally owned by a teenage girl who recognized an easy target:

I introduce Greta Thunberg. Greta, with her keen eye for the tragic flaw that is in Andrew Tate, was able to eviscerate everything about the man in a two-line Tweet. Were Twitter a minor character in a Shakespeare play, the response could be summarized thusly (quoting a soldier in act one, scene two of Macbeth):

They meant to bathe [our enemies] in reeking wounds, or memorise another Golgotha, I cannot tell.

The Internet, I think it’s safe to say, is totally okay with memorializing the crucifixion of Andrew Tate. But it turns out Golgotha is not just a place where Christ was crucified, it might as well be in Romania, where Mr. Tate was hiding out from authorities, after a warrant was out for his arrest for the sex trafficking of young girls:

The authorities allege that two of the suspects misled the victims "into believing that they intended to enter into a marriage/cohabitation relationship" while transporting victims to Romania and later sexually exploiting them with physical violence and coercion.

Authorities also said one of the suspects raped a victim on two separate occasions in March 2022. At least six victims were allegedly "sexually exploited by the organized criminal group," the DIICOT statement said.

The Thane of Tate is able to muster only the weakest of responses, as pictured below:

The tweet itself includes a film. In this short feature film, our hero has a pizza delivered, and reportedly, this same short film provided the evidence for the local authorities to promptly identify his location, and execute the warrant for his arrest. This may or may not prove to be actually true, but it’s pretty hilarious either way.

Mr. Tate simply lives the Shakespearean tragedy:

[He] is but a poor player, that struts and frets it’s hour upon the stage, and then is heard no more. It is a tale, told by an idiot, full of sound and fury, signifying nothing.

The tragic flaw of the Shakespearean tragedies is usually that of hubris. People with enough narcissism, such that it becomes a disorder, fall victim to this regularly. This is what is disordered for people with Narcissistic Personality Disorder (NPD). They do things that are bad for them. They do things bad for others.

Andrew Tate is a gross and awful character. Watching him get this kind of comeuppance is just delightful.

Not All People With Problems Will Be Sympathetic

However, not all people have to be nice to be worth of our empathy.

As a physician trained in psychiatry, I am aware that the genetics for personality disorders and the social environments that make those into disorders giving rise to behavior don’t require everyone suffering to be a sympathetic character.

When we’re talking about mental health, and talking about suffering, we usually focus on the suffering of the individual.

However, if we limit our understanding of psychopathology to mood disorders like depression and we limit our scope of empathy to only relatable individuals, we miss out on the bigger picture.

We benefit if we have empathy for people like Andrew Tate. We don’t need to have sympathy for him. That piece of dirt can just choke on his criminal and hateful manipulation of women and die as far as I care.

Narcissistic personality disorder can cause severe problems—for everyone. Some people are mean and nasty. And those mean and nasty people can do less harm in the world if they get help for the underlying problems leading to the meanness and the nastiness too.

What to Do?

The evidence base for these disorders is limited. We don’t have specific treatments for NPD yet. Our group has published on what attitudes health professionals have toward NPD. These attitudes indicate that mental health professionals aren’t familiar with how to treat NPD, on average. However, with more training, they become more interested in treating the condition. They also find the work more rewarding the more they understand the population.

We have even published on the impact of NPD on response to neuromodulation with TMS. Even profoundly biological interventions, like transcranial magnetic stimulation, suffer from misconceptions around their efficacy in those with personality disorders (our work indicates depression is treated just as effectively with and without personality disorders). But much more work needs to be done to get more evidence based treatments.

We need psychiatric treatments for individual suffering just like we need burn trauma ICUs. Ignoring NPD is like ignoring fire safety and not funding fire departments.

We have heroes in our midst. Women like Greta Thunberg recognize hateful behavior, and don’t allow it to “pass.” Greta recognized that the way we interact with somebody needs to be consistent with our understanding of their mind. She quite clearly understood that this person she was addressing wasn’t gonna handle humor well, and so that’s what she gave him. Her sick burn for Andrew Tate was also her gift to the world.

Narcissistic personality disorder is a disorder for all of us2. The grandstanding of Andrew Tates should be mocked. And the people suffering should be helped.

We ignore narcissistic personality disorder and it’s treatment at all of our peril. Unlike Andrew Tate, ignoring a whole domain of dysfunction in our research budgets is no laughing matter.

is my wife. She loves Sushi. But another thing she loves, I am gonna confide in you, my dear readers, is the appropriate classification of medical procedures in healthcare. She loves codes, such that novel treatments, like accelerated TMS, fits into the rubric of Current Procedural Terminology, otherwise known as CPT codes, a registered trademark of the American Medical Association.

She also, especially, loves Omakase. Maybe as much as CPT codes? But only maybe. Let's start with the Sushi.

Omakase is a way of serving Sushi—it doesn't just encompass the fish on rice itself, or even the maki, which is of course fish rolled in seaweed and rice. No, it's not just that.

Omakase, in Japanese, roughly translates to “I'll leave it to you.” We might call this is chef’s choice menu, in America.

We've had some great Omakase meals in the over a decade we've been together. One of the delight of Omakase? You don't have to choose individual portions of fish. At best, you're choosing the size of the Omakase, do you want eight courses, 12 courses, or 15 pieces of the Nigiri to leave you feeling very satisfied.

You can of course also obtain Sushi at the corner deli, at least if you're in New York. You see that little plastic container? That's got sushi in it. You might even have good sushi! Piece of Nigiri, maybe a little California roll, you can grab and go. You could even buy two boxes of packaged sushi. Or, you can go to a restaurant and order individual pieces, to your heart's delight, and they bring them out all at once. You and your friend get to have a regular meal, the food comes all at once, you chow down, and if you're still hungry at the end, you can order more. There are even “all you can eat” sushi restaurants. They keep bringing you fish!1

What's not factored into any of those a la carte offerings? The experience. Who's making the decision about what you should be served, at what time, and in what order? When you go to a regular restaurant, or a deli, and you order sushi, you're choosing the sushi you want, but implicitly, you're also choosing an experience. And you're not just dictating an experience for yourself, you're a dictating and experience for the chef. Their job is to get you the Sushi as quickly as possible, and your job is to eat it. If you need more, you order more. What what you were explicitly choosing to not have is a carefully timed meal. You're not choosing an experience. With Omakase, particularly an excellent Omakase meal, the service is really part of it.

Boston has one Michelin Starred restaurant, and I'll use that as an example. It’s called 311 Sushi. It's in the ground floor of an apartment building, and it's literally built on top of a garden apartment floor pan. Number 311 on the street.

When you walk in, there's an antechamber, and they take your coat, graciously. Unless it's your time to sit, you won't be seated. This is common in many Omakase, restaurants—they have one, two seatings, and that's it for the whole night. You're not choosing one to come in, you're coming in when the time is right. There's a whole experience ahead of you. At 311, there 10 seats in the entire restaurant. They are all in a row. Here’s what the Eater review reported:

Wei Fa Chen, a Masa alum, leads the 10-seat counter and runs an 18-course, roughly $250 Edomae-style menu. Hidden in a brownstone basement, 311 opened in 2023 and became one of the city’s hardest reservations; Michelin describes the omakase as “impressive nigiri showcasing high-quality product.”

At an Omakase meal, instead of ordering from a menu like a savage in a rush, diners trust the chef to curate a multi-course tasting meal. We leave ourselves at the whim and mercy of the chef—often, similar to medical care, they will ask if we have any allergies. After that, it's up to the chef! This Omakase meal which typically features specially seasonal seafood, magical appetizers, and a course after course of single pieces of nigiri—that’s rice with fish on it— tailored to the chef’s vision for your meal experience.

Omakase Sushi is supposed to have an ebb and flow. Omakase isn’t just about the fish—it’s about the moments between courses. It’s about the experience, the pace, the sequence. The experience is what you are trusting the chef to manage for you. It’s the set and setting of the meal that gets a great restaurant to become…unforgettable.

However, unforgettable birthday dinners don’t just happen. You need the combination of a chef’s ambition, and the right fish, team, and system to deploy each course just so. This allows, along with a credit card reader, the ability to provide unforgettable service and get paid. Every restaurant has a “explanation of benefits” of the meal at the end—they use each piece of fish as a “code” for what to bill you, or maybe they just have a bundled rate. Some restaurants don’t even allow tipping, and the entire experience is included in the tab.

Medical care isn’t that different. Some health professionals are closer, in business model, to a corner deli. Fast, “cheap,” good value per dollar, and they can ring you out quickly so you can “eat and run.” Other medical care is more of a production— Brain Medicine specialists need to perform complex, multi-step procedures. With accelerated TMS, for example, this can include multiple stimulations in a whole day, but the time in between matters too! That inter-session interval is when your brain gets to rest and prepare to change more—and a licensed physician is typically available the whole time to manage what can be a complex experience. Floods of emotions, adverse effects, even surprising joy can well up, and healers need to be available when the change can hit you all at once! Once a day 3- 40 min brain stimulation, on the other hand, works more slowly, and doesn’t involve physician supervised time between treatments.

If we want different medical experiences, like we want different meals, we’d need to have a way to “put them on the bill,” as it were.

The ability to describe the procedures, and submit them to payors for reimbursement, is not a “practice by practice” endeavor. Imagine if all sushi billing was standardized by the Asian Meal Association (“AMA”), and in the Edo period, for example, it was decided that all menus could only include once piece of fish at a time. Bills must be submitted by nigiri piece only, with fearsome Samurai standing ready to claw-back inaccurately tabulated meals. Moreover, a particularly tyrannical Shogun could decide that all tuna should be priced the same! They could, in theory, set standard menus and prices. Whence, then, the more rare and prized Toro (or fatty tuna) portions?

This is what happens in healthcare, in case you are missing the point, or something close to it. Individual doctors can’t just chose to include “inter-session intervals,” with on site MDs, in their billing, without the intervention of the AMA. That is the medical one, not the theoretical sushi menu dominating AMA mentioned above! See, dear readers, how important disambiguation is?!?

We, as healers and patients, want to have the ability to choose what quality of medical experience to provide, what a course of treatment includes, and that just isn’t possible without the right flexibility on the menu. Some practices want to offer all-day treatment with TMS. Others want to offer only once-a-day treatment. Yet others feature fMRI! Others still will use EEG to calibrate treatment.

We need the ability to submit a bill. And, like the citizens of Edo Era Japan, we have to submit to the will of the royal court—except in this case, it’s a committee, called the CPT editorial board. Their AMA doesn’t pay for Omakase sushi, I’m guessing.

Just as even Emperors need to hear petitions, on occasion, so to do we, as “interested parties” get to register and comment on proposed coding changes to the CPT code set. Thus, as treatments change, the code set, that allows for novel treatments, can also evolve.

Here is how you do that, this year, for the AMA’s proposed updates. It’s a time when our voices, interested as they are, can be heard.

The Call to Action

You are asked to consider what makes sense for your practice: coding that supports à la carte or omakase. That’s what the code-writers are actually deciding.

Both proposals go before the AMA’s CPT Editorial Panel (the group that decides what gets a billing code, and therefore what insurance will pay for) this September. There’s an open comment window right now, and it closes August 10.

Here’s the mildly annoying part. You can’t just click a link and read the proposals. They aren’t posted out in the open. To see them, you register as an “interested party” first (yes, that’s the actual term). And an interested party is not just a TMS doctor. It’s anyone with a stake in this: clinicians, patients, families, device makers, researchers, clinic administrators, you. Registering takes a few minutes and commits you to nothing. It just gets you through the door.

Once you’re in, you can read both proposals for yourself, the omakase one (Tab 92) and the à la carte one (Tab 53). Then you decide whether you want to say anything at all.

And “anything” is the operative word. You do not need to be a coding expert. Any reaction is useful, and the most useful one is the honest version: if this became the way these treatments get coded and paid for, how would it actually play out for you and the people you care about?

Register, read, and weigh in by August 10 here: https://www.ama-assn.org/practice-management/cpt/cpt-editorial-panel-meeting-interested-party

Disclosures: I’m a co-founder of Radial, where we deliver accelerated protocols, plus advisory roles at Ampa Health, and I’m the CMO at Neurolief, makers of an at-home Neuromodulation device. I’m not here to tell you what to write. I’m telling you the door is open for you to tell the AMA what kind of menu options you’d like available.

We didn’t get time for a special dinner together, but she asked for an article instead, so here it is. I love you, Carlene. You only turn whatever age this is once.

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“We really need to ramp up our suicide prevention efforts.”

or

“Preventing suicide is really important.”

or

“Zero Suicide”

People say these things. I don't doubt that people mean them. But there are reasons, honest-to-goodness reasons, why suicide is hard to prevent. The system of care we have is faulty at a level that would be unacceptable in any other field of human endeavor.

The Math on Suicide is Merciless.

Suicide is a rare event. The population rate in the US is given in “per hundred thousand” units, cause that's how we deal with rare events. For the general population, it is around 17/100,000. Simply having major depressive disorder increases your risk less than one might think: that number is variously reported as 2,000/100,000 if you’ve had any psychiatric evaluation. Conversely, being admitted to an inpatient psychiatric unit with suicidal depression bumps that number way up, over a lifetime, to 6,000/100,000. To even get these numbers, we need Danish registry data, which falls out like this:

Thank Goodness for Danish Registries.1

Since suicide is a rare event, even if it's differently rare in different cohorts, it's very hard to predict for any individual when it's “going to happen.” Keep in mind, the above numbers are referencing the lifetime risk, so it's really hard to know in any given moment what's the thing that led to death by suicide, versus any other moments in life, which didn't.

In clinical practice, and probably in the life of my non-clinician readers as well, hearing about suicidal thinking is pretty common. For every person who dies by suicide, over 275 people are thinking about suicide at any given moment. 13% of high school girls in the US in 2023 attempted to die by suicide according to the CDC.

So, despite suicide being a catastrophic end that we'd want to prevent, predicting the actual moment at which the end comes in the life of anyone, even somebody who's high risk, is frustratingly challenging. This turns out to be true about every death. We know, with 100% accuracy, than everyone will die. Knowing when anyone will die is, however, a very different undertaking.

Thus, the overwhelming majority of patients evaluated for suicidal ideation are unlikely to die by suicide. They're also highly unlikely to complete suicide imminently. The evaluation of suicidal patients is learning how to address those with an unimaginably high false-positive rate. Psychiatrists do not have a crystal ball. It may also be the case that when we use our broken crystal ball to admit people to inpatient psychiatric facilities, we're actually making the problem worse.

We built a world that discourages disclosure of suicidal ideation for the most at risk.

“Reach out for help, tell someone.”

“Just a few words can be the difference between life and death.”

Ok, maybe, but what happens after you find out someone is suicidal?

The process of being brought into a psychiatric hospital is traumatizing. It doesn't have to be, to be clear. But it is for many people. If you had to get stripped, searched, putting into gowns, locked in a room, separated from your family, all because you had a broken toe? Everyone would be limping.

The heroic people, in my opinion, who walk into the emergency room for help so that they can live even when their brains are screaming that they should die? They are subject to indignity after indignity. Limited visiting hours. You don't get to have a belt—well of course, not, because you could hang yourself? You don't get to have shoelaces. Of course, not, cause you could hang yourself!

This caution is not designed to be a great customer experience. Would anyone, if they didn't feel terrible, choose to go to a psychiatric hospital?

Maybe the answer is yes, but at least for myself, it's the last place I’d want to be.

I don't like McDonald's. I generally wouldn't choose to go to McDonald's, give other options. If my life was in jeopardy? I’d go get an Egg McMuffin. I don't know that I can say the same about psychiatric hospitals.

Would you go to McDonald's if you could be forced stay there? No matter how much you love McDonald's, if you even might be forced, by court order, to stay, and to eat, whatever they tell you…or they're gonna strap you down to a gurney until you relent? How carefully, then, are you thinking about the next trip to McDonald's?

Exactly.

Reducing Suicidal Means is Life Saving. We Refuse to Do It.

Feeling suicidal is often transient. Just ask an ER doctor! Just south of 10% of ER evaluations are for suicidal ideation, but most people are “treat and released.” The feeling that one wants to die can rise up, sometimes gradually, sometimes like a tidal wave, but in most cases? It passes. Putting time and friction between the thought that one should die and the act that could lead to death is a proven way to reduce suicide.

We’ve tried means restriction, that is restricting access to lethal means for people who might be thinking of it. We should do more of this. It would, however, take acknowledging realities like “ready gun ownership everywhere all the time” puts more people at risk of death by suicide, and that's just not the country we live in, here in America, even if it is the case of other places in the world.

We Do Not Measure, At Our Peril

Only 16% of psychiatrists us any rating scale whatsoever in the initial visit. Only 8% use one thereafter. Imagine trying to master flight without knowing how high you were above the ground. Or imagine trying to fix visual humanity without measuring which glasses we should stick on someone's face. Now stop, imagining, cause you're living in the mainstream of psychiatry. We built an entire field of medicine on vibe checks. It's going as well as you would imagine.

Your author loves a rapid acting treatment. Heck, we have a whole event series dedicated to them, with the next RAMHT event happening at Psych Congress, on September 14th, 2026. Get your tickets now!

RAMHT @ Psych Congress

We Put the Most Effective Treatments Last-In-Line.

Lithium has data for the prevention of suicide. One drug, Clozapine reduces risk for suicide in randomized trials. SAINT has signal that it may be able to reduce suicidal ideation rapidly. TMS and Ketamine…you get my point. The most prescribed medicines in psychiatry are benzodiazepines, which might increase risk, and oral antidepressants, which at least increase the risk of thinking about suicide in youth. We put the good stuff behind the glass, with the lock and key, and keep the dangerous or infective treatments first line.

At best, oh gosh, we're going have to wait for prior authorization! Don’t get me started.

Suicide Prevention, at Present, is a Bad Product

Suicide is not a disease. It's a final common pathway. The problem is human suffering. We are not asking the right questions. Instead of asking “how we can prevent suicide,” we should, perhaps, be asking how we can identify suffering, ameliorate, suffering, prevent suffering, and—here is my provocative bit— do so in a way that's appealing to everybody?

Preventing suicide is only hard, in part, because the math is challenging. It's a rare event that we're bad at recognizing and catastrophically bad at addressing when we recognize the risk. But we also need to recognize that many of us didn’t understand the assignment is the prevent suicide so that the risk goes down, relentlessly.

Let's make getting help for suicide a great customer experience. Then, everyone will want suicide prevention treatment. Because, and I know this sounds outrageous, but having a great experience with a suicide prevention approach would make you more likely to prevent suicide for yourself. You might even recommend suicide prevention to a friend.

In maybe completely unrelated news, there's new FDA guidance on research into psychedelic medicines…

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