In the pandemic, I didn’t know what to do with myself. One of the things I did to make sense of my world falling apart was to make a podcast. I think the questions I asked at the time hold up well enough. This is the first episode I made, just about a week into lockdown in New York City. I recorded the audio on March 13th and released it on March 15th, 2020.

Frankly, the worst thing about how we handled the pandemic was how we explained things—and this lack of focus on mistrust engendered as a public health risk is an enduring legacy. I called the show “remotely possible.” This is a photo of the first recording setup on my kitchen table.

Let me know what you think, with the distance we have now. There are more of these. I’ll release them in this feed.

Thanks for reading and listening.

This is an interview from 2015 with Samuel Sharmat, M.D., a brilliant diagnostician. It also was an interview that, in retrospect, helped define my options as a physician. He has a traumatic brain injury as a young child, it changed him. For him, the change unlocked new ways to notice what might be wrong with patients in ways that others could not. Please listen, and share with your friends.

I won a grant years back to produce a podcast series from NYU’s Rudin Master Scholars Program in Ethics and Humanities. I am proud of that work. This episode never made it on the air. It is presented for your consideration. Suicide is discussed, frankly. Both my friend and guest, Lara J. Cox, M.S., M.D, and I discussed extensively that her name should be used. That personal disclosure was the healing element, as we understood it.

I presented this work on May 6th, my birthday, in 2018, at the APA annual meeting. That morning, a psychiatric resident in a local program died by suicide. It was devastating. This is a challenging disclosure to write— because of my worries about contagion effects. This issue around contagion was the difficulty in editing these stories to begin with.

These stories aimed to REDUCE suicide risk by providing stories of hope. These stories offer support for vulnerable medical trainees. Otherwise, they learn the lesson…as part of the hidden curriculum of medical training:

“It’s unsafe to talk about your struggles, even in the past.”

We lose hundreds of physicians to completed suicide every year, and the numbers on ideation are dispiriting:

A 2015 meta-analysis of 54 studies examined the prevalence of depression and depressive symptoms in resident physicians across decades and around the globe.2 They found a 15.8% increase in depressive symptoms during the first year of residency, across all specialties and countries of training. Over the course of training 20.9% to 43.2% of residents reported depressive symptoms, with symptoms increasing over time. This finding could be extrapolated to fellows, attendings, and other post-training physicians. Currently, the actual data for post-training programs is sparse.

When we refuse to speak—using best practices—we are also heard. I have long argued this is not the way.

The physician interviewed in my podcast above is brave, outspoken, and a personal hero. Lara J. Cox, M.S., M.D., has served on the Board of Trustees of the American Psychiatric Association and is herself a scholar of suicide prevention.

I won a grant years back to produce a podcast series from NYU’s Rudin Master Scholars Program in Ethics and Humanities. I am proud of that work. Here is one of the episodes that NYU “Doctor Radio” felt was a touch too edgy…

I’d love to make more, but this production isn’t cheap!

Thanks for listening, and share with your friends—a special thank you to Lancy Levy, R.N., my guest in this episode.

The Frontier Psychiatrists is a newsletter. It's written by one Psychiatrist, Owen Muir, M.D. It's a health-themed newsletter. It's also an exercise in imperfection. That imperfection is not an accident. Here is the story…

An influential book in my life? It is not about medicine. The book is called Measure What Matters. It is by John Doerr; you can buy it on Amazon with that link!

John writes about the system called objectives and key results (OKRs). Andy Grove originally developed this management and goalsetting methodology at Intel.

I think it's a meaningful bulwark against perfectionism. It is a philosophy. OKRs are a system for setting measurable goals. But—there is a quirk. This quirk makes it different—and more powerful— than other goal-setting approaches. The system works as follows:

* set an overarching objective, and the point is to be audacious.

I'll give you a very real-world example:

“I'm going to write a great health-related newsletter (all by myself) that influences people’s decision-making towards a better future.”

Now, here's the trick: you have to figure out how to determine if you're moving toward that goal. And it has to be measurable. When you start this process, you don't necessarily know the best way to measure things for yourself or a larger organization; this is the scaffold.

There are rules:

* At the end of your audacious goal, you add the statement: “as measured by:”

Next, you limit yourself to between two and three (easily) measurable key results demonstrating that you are appropriately pursuing that goal. The quirk is

* if you achieve more than 70% of your key results in any given quarter, you did it WRONG. Getting it perfect means you didn't get it RIGHT.

My God, right?

This is a system to learn how to set audacious goals! I could've set my goals for this newsletter— and did— as follows: “as measured by… publishing an article every single day.”

That is a “key result.”

This is not the same as a key performance indicator (KPI). Key performance indicators are measurable. Some, however, are all or never—you don’t want to close 70% of surgical wounds! Many things are measurable; not all KPIs are useful tools in this OKR framework.

All Key Results are KPIs; not all KPIs are suitable Key Results for your strivings.

I write an article almost every single day. I will calculate that for my readers at the end of this quarter, and you can see how I did. I didn't know what key results were the best way to build an influenced audience with this newsletter. Did I get it wrong with this key result? First, I have achieved the goal more than 70% of the time! I underestimated the difficulty, and thus the audaciousness, of a daily one-person newsletter for me as a writer.

By writing a daily Health-themed newsletter, I failed to be audacious enough! Or I didn’t select the right tools with which to measure. I would probably want to set another key result to guide me when I revisit the original goal and its measurement. Which is very much the point. OKRs are not “set and forget”. They are set and revisited. It’s an iterative process. We learn, with OKRs, that successfully striving is the meta-goal. We know if we succeed by measuring iteratively, and in failing to be perfect, we learn the right degree of stretch in any epoch.

Perfection is imperfect. Striving is a learned behavior and a set of skills. Not always striving is an easy way to avoid the audacious. In my example, my daily publication schedule might not be the best way to achieve my goals.

I’d have to find a better way to measure. Repeat.

Perfection is poison for those who wish to strive. To succeed at striving is to fail… the right amount, over and over. OKRs are an antidote to the hopelessness of perfectionism and the fragility of narcissism.

Do you have any idea what mental health is? I wish I did. You have permission from me to be confused. I’m Owen Scott Muir, and I’m a Mental Health Professional. I should probably have an idea. I refer to the Frontier Psychiatrists Substack as a Health-themed newsletter for all the reasons I’m going to enumerate. Subscribe.

We've been told mental health is important. It is. I don't know what the word it means in this context.

Or I would like to know if we have a shared understanding of the word we would accept be acceptable in any other conversation. If we ask if your car is OK, we have a general sense that the car would need to have:

* structural integrity,

* four tires,

* the ability to move on those rolling tires from one place to another,

* not breaking down constantly, and

* not crashing into a wall.

Working tires, wheels, and the ability to move someone from one place to another are all accepted concepts regarding the utility of anyone's car. Cars need to go… safely.

Health, as a more broad term, is better understood. Are you actively dying? Are you in pain? Are you able to breathe? Is your heart beating? Can you get out of bed, comb your hair, brush your teeth, go to work, and hug your children? Activities of daily living have been defined.

I fear we made a mistake by putting the word mental in front of the health. It's confused us. Because it suggests there's something different about mental health and health. Health, the state of well-being in which one can do the things they need to do in the day without significant impairment, is a meaningful way to assess whether someone's health is good enough. Being functional, you don't need the word mental in front of it.

I would encourage us to consider Health on this World Mental Health Day. I would encourage us to think about the distinction between disability by any standard and what would be the ability to do life things by any measure. The brain is part of the body. The health of the brain and its relationship with the body matters. Similarly, the health of your body and the health of the bodies and brains of the people you interact with matter.

I urge researchers and clinicians to look at ability and disability broadly.

* Are you able to focus?

* Are the things on which you can focus the things you'd like to focus on?

* Can you have positive, loving relationships in your life?

* Can you do meaningful work?

* Can you pursue a goal?

* Can you imagine feeling satisfied?

* Can you work towards feeling satisfied, perhaps in an accessible educational setting?

The further we get from the confusing specifier of mental before the word Health, the better. It is about addressing disability. We happen to have laws about that, at least in the US.

Healthy people are mentally healthy people. Being mentally healthy doesn't do much to add relevant context, and I fear that it subtracts some from our ability to understand each other.

Thanks for joining me on this World Health Day, which is maybe what we call it in the future.

This is an episode of the Frontier Psychiatrists Podcast. It’s a conversation between my Fermata team member, Chelsey, and Myself. This conversation is about us, at work, trying to understand neuroscience together. We recorded this one! An edited version of the transcript follows.

Owen Muir, M.D.: So we were chatting about the amygdala, and if you want to ask me any questions about it, I can answer them and edit it together. And that's a podcast.

Chelsey Fasano, BA: There's a lot of discussion in the field right now about location neuroanatomy or chemistry neurobiology. And I'm always thinking about how the two crossover, so we're talking about the up-regulation or down-regulation of the amygdala.

What are the neurochemical aspects of how the amygdala would be up- or down-regulated?

Owen Muir, M.D.: Neurochemistry is a great way of selling drugs and selling explanations that are easy to understand.

When we talk about neurochemistry, we're talking about a synapse between two nerves that are trying to communicate. There's a tiny little gap, and the way a nerve communicates with another nerve cell is a neurotransmitter is released from one and floats its way across a tiny little gap, and then hits a receptor on the other side, and that creates a change in that subsequent cell, which makes it either more likely or less likely to fire.

What's happening next is within that cell. There are intracellular changes that lead to an increasing likelihood of reaching an action potential and itself firing and effectuating the next change in its neighbor cells. We focus narrowly on neurochemistry, because we can look at and modify it.

We're getting obsessed with answerable questions— not with important questions. For example, we don't give people “hyper-glutamate,” the excitatory neurotransmitter in the brain. They'll have a seizure.

Those excitatory impulses open ion channels that cause immediate depolarization and firing of neurons. Uncontrolled depolarization leads to seizure and death. GABAergic drugs do the opposite thing. So, anything binding to the GABA receptor opens a chloride channel. Chloride's negatively charged.

And that changes the inside of the cell's voltage to negative, which means it's less likely to fire because you need more glycine and glutamate to increase the voltage. GABA is safe to agonize, because you're not going to get a seizure—but withdrawal is dangerous because now you're more likely to fire in the absence of the GABA drug.

We're focusing on other compounds like serotonin, norepinephrine, and dopamine, which functionally regulate the internal cellular environment, making firing more or less likely. And we focused on it because it's safer.

We got obsessed with what we knew we could do and not immediately kill somebody— as opposed to what might actually be effective or is happening naturally because, on their own, our cells are firing and releasing neurotransmitters and pulling them back up and regulating their voltage without us messing with it at all.

For example, the chemistry argument at the amygdala level is part of the story. But when we're talking about what information the amygdala is kicking out, it's really how fast it is firing. That's my kind of argument. It's a rhythm answer.

If we looked at the stage plot for AC/DC and saw they had a lot of cables and started worrying about which cable plugged into the guitar as opposed to they are going to play in time --and you can replace the strings, the guitar, the cables. You do not have a good AC/DC show if they play at a time, and if they're playing in time, even if the guitar cuts out like bass drums, Angus is still locked in, and it rocks.

We've focused on what's focused-on-able, not what matters.

Chelsey Fasano, BA: The primary neurotransmitters of the amygdala are precisely the ones you were talking about!

Owen Muir, M.D.: The n methyl D aspartate receptor is a binding site that modulates glutamine.

Chelsey Fasano, BA: So that makes sense as to why ketamine would strongly affect PTSD since it works primarily on NMDA and GABA. That would downregulate the amygdala, which would help to buffer against the overactivity associated with PTSD and subcortical areas.

Owen Muir, M.D.: The firing rate functionally comes down because each nerve in the amygdala firing becomes less likely by some amount.

Chelsey Fasano, BA: Is the feeling something to this whole hippie thing of vibration and vibe?

Owen Muir, M.D.: It's true at the level of the neurons in the brain. Yes. I think wavelength is an accidental term. I don't know. But it's the literal truth.

Chelsey Fasano, BA: We know that neural firing from some research that I've read affects motor movements and speech patterns, and so there probably is some truth to the fact that upregulation of specific circuits is going to cause speech pattern and motor movement differences that are going to be the bodily rhythmic reflection of the brain activity. We would pick up a vibe because we all sense those things about each other through our brains.

Owen Muir, M.D.: We're building a model of the vibe. I propose that a firing pattern represents everything in the brain. It's click click of one nerve group, right? And in the other person's brain, it's click click.

But in our brains, we build a model of our click. And then, we make a model with clicks in our neurons of the other person.

We're constantly building models of other people's minds in our minds with our pattern of firing. Then, we pick up signals from their motor movements and behavior. We're resynchronizing our model. with their model, and we're constantly just getting it a little bit wrong and getting back into sync, and what humans love is feeling in sync.

When we dance, we're dancing in time. Like the guy who dances badly, we find displeasure. When we dance together, we find it joyous. When we're dancing to the beat, we enjoy that because our brains all represent the beat simultaneously. We can look and see and feel with high bandwidth sensory cortex and high bandwidth motor cortex that we are together, and that lets us not bump into each other when we're dancing and emotionally not bump into each other's feelings when we're communicating.

The dopamine system, for example, which profoundly regulates ventral striatal activity around motor gating, is also implicated in not just motor gating but also the gating of behavior. Some of that behavior is our feelings, how we react to the feelings, and how we talk, think, or sing.

This is how we can do things like lie to each other politely and not get enraged. Because there are times when someone lies to you, and it's bad, and how dare you lie to me. There are times when someone says, thank you so much for calling. And we recognize that their thanks may not be sincere.

And both of us are definitely on the same page about that, but the underlying intent we have modeled for the statement is beneficent.

We're both on the same page about that metadata, which is, oh, the person's lying to me, but it's because they care and want me to feel good. And so I'm going to think this lie is kind in this context, and in other contexts, my internal model was that they shouldn't have lied as opposed to should have lied.

So it's not the lie; it's the intent that we model and can reconnect to that allows human behavior and motion. To go well. If someone's a lousy dancer because they have Parkinson's, you're not going to love it, even if you don't know they have Parkinson's, and you may feel more positively inclined to them if you understand they have a reason for it.

But it doesn't feel good. We feel good when we move together.

Chelsey Fasano, BA: We've had some discussions about this previously about you not valuing agreeableness or not liking that quality of when people pretend to be polite, and I tend to be more like that.

And I think when I do that. Often, when I attempt politeness or I attempt positivity, even in a situation where things feel pretty dire, and I don't think that way, what I'm doing, my intention, is I'm trying to slow down the dance. I'm trying to introduce something to the dyad that I'm a part of that is not necessarily totally authentic in that I'm not feeling it at that moment, but I want both me and the other person to handle it.

I desire. So, I create the desired state in affect, hoping the dance will move in that direction. It often works. If you fake it till you make it, and you choose grace, and you choose to give someone calmer and more positivity than you might feel like they deserve, they often follow suit by giving it back to you.

Owen Muir, M.D.: What mentalizing and Peter Fonagy would say about this is like the way to do that most successfully because some people will interpret it because their experience and trauma, for example, as a lie—an aversive lie— and that'll create mistrust, and they'll get agitated, right?

Like, how dare you be polite to me, right? For those individuals and people who like politeness, you can do the same thing: mark your intentions. I'm going to be polite now. It's just that much—set it up. “I am behaving in a way because I hope it will be helpful.”

You can tell me if that's different from how it comes across. You can do whatever you want, and you have the spoonful of acknowledging the rationale for your behavior that gives them the additional information that you're doing it within the intent of XYZ, as opposed to just being polite. They can assume you're scamming them with your politeness.

Because they're people who've been harmed, scammed, and traumatized by polite people who wanted to abuse them. Thus, politeness for them may be a signal of risk. And so it's the ability to mark that I wonder if politeness is the right way to go, but I will try it out. That is the kind of permission slip to behave; however, you need to behave and also eat if it goes poorly… in a tolerable way.

“Wow, my politeness came across badly there. I can see by the look on your face that politeness was the wrong approach,”

Then suddenly, they feel understood and don't want to argue with you anymore.

Chelsey Fasano, BA: We've talked before about having a mini version of the other person in your head, which, according to this conversation, the mini representation of the person that we have would be not only our conceptions of them and abstract representations but be a literal rhythmic firing of neurons, which explains sort of emotional contagion and how you can feel someone else's feelings.

Owen Muir, M.D.: Mirror neurons are a metaphor for mirror patterns of circuits firing

Chelsey Fasano, BA: When we're looking at different schools of therapy, and some people are saying all of the feelings that you're feeling are definitely counter-transference are all coming from your past. It sounds like what you're saying is that's not accurate. What is happening is that we're getting rhythmic representations of the person that are combining with the conceptions that we previously had of what those rhythmic representations mean to create a sort of mini person inside of us that then informs both Our immediate affect as well as our ability to predict another person's behavior across time.

Owen Muir, M.D.: a million percent correct. So it's yes. Therapy is neuromodulation using the sensory experience of another plus the representation they have of us and the representations we have of them, and the desync/resync on repeat —is what therapy is. If you've seen projective identification when you come across that term, the ability to invoke in another person Psychodynamically a behavior that's true because of my ability as a human to create a model of you and perturb that model and react to the perturbances. I see it in a way that's in keeping with my internal representation.

It's a fish swim in schools. They're not sending a letter to all the other fish in advance, being like, okay, so in second 17 — turn left. They're modeling all of the other fish and then swimming in context with the model and then adjusting the model in each fish, so there's the constant adjustment of how much the school is moving because we're all building models of the school and checking them with each of the nodes in the network.

In therapy, you have a dyad that's doing the same thing. I move left, and I expect you to move right, and you move right as far as you move right. And then that hits or doesn't hit the model I have, and then we move back to the center and do it repeatedly. That's the misunderstanding that is the neuromodulatory agent in psychotherapy. Still, it's brain rhythms in both people's brains firing and then checking, and error checking against the visual sensory interpretation as presented to consciousness and heavily edited by subcortical structures that make that dance happen. It's the getting it wrong, just like in meditation, -- we're attending, losing the attention, bringing it back to the flame. And bringing it back to the flame is why we meditate, not simply “staying on the flame.” It's supposed to be challenging.

It's better if it's hard because it's a workout. -- Therapy is better if it's hard because it's a workout. But it's not just for attention regulation; it's a process of re-syncing to better inter-human and intra-personal things because when you do it in therapy, you get to do it out in the world when the therapist isn't there to help. So, being a therapist who's a little bit wrong all the time and then gets back to it is the honest answer. Ta-da! How's that?

Chelsey Fasano, BA: Good.

Owen Muir, M.D.: Let's see if it turns into anything.

Welcome to the most exasperated column yet in the ever-expanding Frontier Psychiatrists’ pharmacopeia of the gosh-darned. This is a daily health-related newsletter, and there is a lot behind the paywall (most writing past 5 weeks old)—consider subscribing and buying coffee makers I like from Amazon to support the work.

Other Include Risperidone, Depakote, Geodon, Ambien, Prozac, Xanax, Klonopin, Lurasidone, Olanzapine, Zulranolone, Benzos, Caffeine, Semeglutide, Lamotrigine, Cocaine, Xylazine, Lithium, dextromethorphan/bupropion and Adderall, etc.

TL;DR?

The world doesn't need Paxil.

Paroxetine is another SSRI. I have never prescribed it. If I had ever needed it to exist, I probably would have. Like Xanax, they got it over the line with panic disorder as an indication. This alone should have been a red flag.

It’s got a viciously short half-life. It’s got tons of awful adverse effects…

paroxetine was associated with a 620 percent increase in the rate of breast cancer in women who had taken it over a four-year period

Following this thread, which lands amid “eh-I-don’t-know-ville,” then takes you down a fiendishly complex rabbit hole of human biology. The genetics for why Paxil sucks are complex:

As many of these genes lie in the major histocompatibility complex (MHC), paroxetine may have downstream disruptive effects on synaptic pruning and over-editing of brain connections as well as polymorphic gene induction resulting in single nucleotide polymorphisms (SNPs) or even tri-nucleotide repeat polymorphisms (TNPs). This is speculation, but theoretically consistent with what is known about these phenomena.

This is complicated but probably not true of other oral antidepressants. I am a “smart doctor,” probably. Even I have precious little idea what the hell the authors are trying to say in the above paper other than “it’s complicated.”—like a Facebook relationship status in the late 2000s (h/t ) or an SBF explanation (h/t ) of the “where the money went.” (h/t ).

Paxil: It is to SSRIs what the FTT token was to cash money. It is conceptually related. BUT…didn't need to exist.

I was going to do a big long thing, like I do. I might still. In the case of Paxil, much like the brutal withdrawal phenomena, less is more. The following is the actual title of an academic review paper:

Paroxetine—The Antidepressant from Hell? Probably Not, But Caution Required

Paxil. I. Just. Can’t.

—Owen Muir, M.D.

The Frontier Psychiatrist's newsletter? It is what you are reading. It’s a health-themed publication written by Owen Scott Muir, M.D. This is a brief detour from my recent series on medications, many of which have a critical slant. Those include Risperidone, Depakote, Geodon, Ambien, Prozac, Xanax, Klonopin, Lurasidone, Olanzapine, Zulranolone, Benzos, Caffeine, Semeglutide, Lamotrigine, Cocaine, Xylazine, Lithium, dextromethorphan/bupropion and Adderall, etc. I write this all by myself every day. Consider subscribing. (the paywall starts 5 weeks back, and there are 360something articles back there). It makes a horrible or awesome gift, depending on your friend circle.

I also get paid more money by Amazon if my readers buy stuff now, like, for example, my favorite book about mental illness—or this tea I drink daily. I also encourage you to send me this coffee maker— or, more realistically, to anyone else.

Today, I address what happens when schizophrenia is not treated, even if it is. It has high morbidity and mortality, a problem that medications address. Effectively. Not without costs, but the best data suggests treatment is better than no treatment for most people.

I’m going to cut to the chase briefly, and if you or a family member want to read a great book on treatment with antipsychotic medicine, I’d recommend this one. Jeff Leiberman, M.D., has been …controversial… of late. However, there is no denying his role in understanding schizophrenia and its treatment, and his book on the topic is worth a read or listen, called a Malady of the Mind.

Psychotic. We use the word commonly in chit-chat to denote something is bad. Unreasonable. Wrong. Deranged. Nothing is beguiling about the word. It is a thing to deny in oneself— “I am not psychotic!”

Understanding Psychosis

Some people don’t get that luxury. Some people are honest-to-goodness psychotic. Most of us do not know what that means. Some of us do, and some smaller portions are blessed with the ability to spend time on both sides of that psychotic equation. I will define the term:

Psychosis refers to a collection of symptoms that affect the mind, where there has been some loss of contact with reality. During an episode of psychosis, a person’s thoughts and perceptions are disrupted and they may have difficulty recognizing what is real and what is not.

The most common illness we associate with psychosis is schizophrenia. Psychosis can occur with depression, bipolar disorder, and other maladies. Depression and mania are mood states; we refer to these mixed with psychotic symptoms as affective disorders in psychiatry. A brief grammar note, brought to you by Grammarly, a tool I use and—sadly—am not paid to promote:

Is affective just another word for effective? Are the two words similar and entangled in the way the verbs affect and effect are? No, affective is not just another word for effective. And affective and effective are not derived from the verbs affect and effect. They come from the nouns affect and effect.

There is a difference in the literature—and in the lives of patients—when it comes to illnesses that have affective psychosis and non-affective psychosis. Much of the anti-psychiatry crowd focuses on affective disorders and argues about the side effects of those treatments. Less attention is paid to non-affective psychosis because It’s not as compelling an argument. These are challenging illnesses either way and are associated with significant morbidity—impairments in life—and mortality—early death.

“Uncured of Worse”: 1937.

As far back as 1937, authors noted the grim prospects in the long-term course of schizophrenia (in this context, I’m referring to largely “non-affective psychosis” —where the delusions or hallucinations are not tied to mood episodes):

Of the 100 cases, 66% were uncured or worse after the lapse of 6-10 years, with persisting process symptoms or in a defective state after the course had run; 13% were improved, 4% were cured with defects, and 17% were completely cured.

“The Prognosis is Poor”: 2010

By 2010, with decades of more data, the conclusion was much the same—schizophrenia sucks, even compared to other admittedly bad illnesses:

Our 26-year longitudinal study and other longitudinal studies confirm older views that outcome for schizophrenia, while showing some variation for different schizophrenia patients, is still significantly poorer than that for other psychiatric disorders.

A large NIMH follow-up study with 2 to 10 years of time following patients from a first episode that required hospitalization demonstrated:

The sample showed substantial functional impairment and levels of symptoms, with only about 20% of the sample demonstrating a good outcome…

The “not-good” outcomes looked like this:

78% of the sample suffered a relapse, 38% attempted suicide and 24% had episodes of major affective illness.

Beyond Psychiatric Problems?

We tend to focus on the role of bad psychiatric outcomes as psychiatrists. Still, the medical outcomes are similarly troubling, including high smoking rates, metabolic syndrome, heart disease, HIV, Hepatitis C, and other medical illnesses. Overall, this leads to an extremely disheartening finding: having schizophrenia is an illness that takes a tremendous toll on the individual and their family and leads to early death and disability at unacceptably high rates:

Persons with schizophrenia have an exceptionally short life expectancy. High mortality is found in all age groups, resulting in a life expectancy of approximately 20 years below that of the general population. Evidence suggests that persons with schizophrenia may not have seen the same improvement in life expectancy as the general population during the past decades. Thus, the mortality gap not only persists but may actually have increased.

Comparisons are useful, and if we look at HIV after the introduction of HAART (Highly Active Anti-Retroviral Therapy), we find:

HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003).

And if we compare that to schizophrenia, in the largest meta-analysis I could find, we find:

The mortality risk for patients with schizophrenia was 1249 per 100 000 … (95% CI, 1029-1469)

Psychosis is Bad Compared to Other Bad Things

The mortality from schizophrenia is 19,215% higher than from pre-HAART HIV infection and 96,076% higher than from HIV with HAART treatment.

If you had to choose between HIV and schizophrenia, HIV is safer—with or without treatment.

To make the point even more clearly, even having a car crash only has a 0.77% fatality rate, or 770/100,000.

If you had to choose between a car crash and schizophrenia, the car crash is safer.

Those outcomes are not good enough. Schizophrenia is impairing and dangerous to your life, especially if untreated. Other psychiatric illnesses are also. Psychiatric medications can modify this risk to your life in the right direction, even with those risks. Tapering them, as we saw in the RADAR trial (lead-authored by a critical psychiatrist, published in the Lancet just this week), doesn’t make it better:

At 2-year follow-up, a gradual, supported process of antipsychotic dose reduction had no effect on social functioning.

And, further, made it worse:

here were 93 serious adverse events in the reduction group affecting 49 individuals, mainly comprising admission for a mental health relapse, and 64 in the maintenance group, relating to 29 individuals.

It includes twice as many deaths. In a research study, this is a huge deal. The way to look at this is the probability of relapsing is bad, and it’s statistically more likely and with more than double likelihood if you were randomized to a taper protocol.

Antipsychotic Medication Saves Lives. It has Burdens. These Choices are Difficult.

We need to do better, but the haters are incorrect. We have done better than nothing, even with imperfect tools, even when examined by those who have an axe to grind with those very tools. Treatment of schizophrenia saves lives.

Stay Humble,

Faced with Suffering,

and Carry On

—Owen Scott Muir, M.D.

My favorite opening line of an academic article (this week) follows:

Mental illnesses are prevalent, cause great suffering, and are burdensome to society.

Welcome to the Frontier Psychiatrists. It’s a newsletter that I write all by myself. I’m doing a series on medications, largely (but not entirely) in psychiatry. I’m a child and adult psychiatrist, and I still see patients. I’ve also been a patient since I was 16 years old. Please consider subscribing and sharing widely.

The first antipsychotic introduced after clozapine would be a big deal—especially if it didn't cause life-threatening side effects. Risperidone was first developed by the Johnson & Johnson subsidiary Janssen-Cilag between 1988 and 1992 and was first approved by the FDA in 1994. It’s one of the very few drugs with data for bipolar disorder that I, personally, have never been prescribed.

Risperidone—Risperdal as a trade name—was ready to be a huge hit.

It was presented as very atypical—this was the post-clozapine branding of choice. The “second generation” label was added years later. I have a confession to make. After residency, when the attending doctors told me, as a trainee, what to prescribe, I never prescribed risperidone ever again. I think this compound—and paliperidone, the metabolite— still has an important role in managing schizophrenia and bipolar disorder. There are more formulations of long-acting injectable risperidone and related compounds than I can remember. I think those are going to be useful drugs for a long time. Oral risperidone? Nope.

Clozapine was an exciting drug. No horrible motor side effects? (Plausibly) More effective? It was better than every drug that came before. It had this pesky adverse effect that could lead to death called agranulocytosis, which I addressed in my first research paper in 2011. We needed more drugs that were this atypical!

We—the field of psychiatry, at least— needed things that were not gonna kill you abruptly, in a terrifying manner, like clozapine had the rare potential to do. But we didn't want more of the same old antipsychotics. After Psychiatry got a taste of not having to explain permanent tardive dyskinesia as a likely side effect of antipsychotic medication, we wanted to keep doing that. Editors note: It is still a side effect of all non-clozapine antipsychotics, and we should never have let our guard down.

Risperidone was the first antipsychotic that came to market after clozapine rocked the world of psychiatry by being better. Risperidone is similar, and they even use the accidental branding of clozapine— “atypical”—for this medication.

The Food and Drug Administration (FDA)-approved indications for oral risperidone (tablets, oral solution, and M-TABs) include the treatment of:

* schizophrenia (in adults and children aged 13 and up),

* bipolar I acute manic or mixed episodes as monotherapy (in adults and children aged 10 and up),

* bipolar I acute manic or mixed episodes adjunctive with lithium or valproate (in adults)

* autism-associated irritability (in children aged 5 and up).

Also, the long-acting risperidone injection has been approved for the use of schizophrenia and maintenance of bipolar disorder (as monotherapy or adjunctive to valproate or lithium) in adults.

The “mechanism of action” of all of the drugs that have efficacy in psychosis was presumed to be dopamine D2 receptor blockade, a mechanism shared with all of the prior medication from Thorazine (chlorpromazine) through Haldol (haloperidol). The assumption—which clozapine disproved—was motor side effects were required for the drug's efficacy in psychosis. This primacy of the D2 blockade as a mechanism of action has since been disproven. This is the mechanism that leads to gynecomastia, leading to a bevy of lawsuits from men who developed breasts. It also causes related side effects like galactorrhea—breast milk from breasts that can be on men or women who are not nursing— and erectile dysfunction.

Dopamine—it does a lot of work in the brain, not just pleasure.

This motor side effect profile was not true with clozapine. It had various additional receptors, particularly in the serotonergic family (5HT-2a, for example), and alpha-adrenergic, histaminic, and other receptor sites throughout the brain.

This broad profile of different receptors explains the wide range of side effects. But more importantly, these are complex, “messy,” and hard-to-predict outcomes given the complexity of the brain. The complex pharmacology allowed psychiatrists like me to think—hard!—about which particular witches brew of receptors we would choose to tickle (agonize) or antagonize. It’s very satisfying. I also suspect this is a story we tell ourselves that is not as closely moored to truth as we’d like. We enjoy thinking about science-ish stuff. Receptor binding profiles are seductive— because they are knowable. Our patient’s heart, hope, dreams, and heartbreak? Less so.

The most important feature of risperidone today—and its 1st order metabolite, paliperidone—is that is deliverable as pills, rapid-acting dissolvable tablets, and long-acting injectable formulations, lasting between 2 weeks and 6 months between doses.

A psychiatric treatment that isn’t an oral once-daily pill? One you have to take twice a year? Medicine that is intended for people who often—like many—feel conflicted about taking a daily pill? That is a big enough deal. That is a real innovation— it considers human frailty, ambivalence, and common failures of mind. Not because it’s a magic drug. Rather, long-acting medicine that doesn’t make crippling relapse easy —thanks to good design— is exactly the kind of medicine that works. My second research effort was on the acceptability of such medicines in youth. It’s responsible for my presence at the academic conference where I met my now wife.

Oral medicines were popular because they were easy to sell. Novel medicines and technologies will be easy to take. The story of my fascination with the risks and benefits of these medicines doesn’t end there, though.

I still research these medicines and their adverse effects— funded by NIMH— for identifying Tardive Dyskinesia with Machine Learning and closed-loop Internet of Things physical medication compliance tech with my team at iRxReminder and colleagues at Videra. We are enrolling in a study at Fermata in New York and other sites.

Thanks for reading.

This article is another in my series about one drug or another. Prior installments include Depakote, Geodon, Ambien, Prozac, Xanax, Klonopin, Lurasidone, Olanzapine, Zulranolone, Benzos, Caffeine, Semeglutide, Lamotrigine, Cocaine, Xylazine, Lithium, dextromethorphan/bupropion and Adderall, etc.

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One way of supporting this publication is buying stuff from Amazon, like a nifty box from Apogee that I used to record the voice-over: the BOOM. In fairness, it’s just the A/D. I am also using the API 512c mic pre, plugged into an AnaMod 660 500 series compressor, nestled in a reliable RND R6 Lunchbox, and all of that plugs into the Boom into my Mac. It’s a Microtech Geffel mic. Most of the audio post-processing is done with Izotope RX 10. I get money if you purchase any of these things— not a trivial amount since they upped my affiliate rewards.

In case anyone was wondering if I was an audio nerd…