Psychiatry & Psychotherapy Podcast - The History and Use of Antipsychotics

Episode Date: June 19, 2018

In the latest podcast, Dr. Cummings and I talked about antipsychotics, the particular branch of psychopharmacology that deals with medicines that treat psychotic experiences and other mental disorders, such as: Schizophrenia Severe depression Severe anxiety Bipolar disorder Psychosis exhibiting hallucinations and delusions By listening to this episode, you can earn 0.75 Psychiatry CME Credits. Link to blog. Link to YouTube video. Join David on Instagram: dr.davidpuder Twitter: @DavidPuder

Welcome to the Psychiatry and Psychotherapy Podcast, the podcast to help you in your journey towards becoming a wise, empathic, genuine, and connected mental health professional. I'm your host, Dr. David Puter, a psychiatrist who splits his time practicing psychopharmacology, individual and group psychotherapy, medical director of a day treatment program, medical education research, and teaching, residents, and medical students. Okay, we are live, and I am back with Dr. Michael Cummings. And today we are going into part two of sort of a review of psychopharmacology. We're going to be diving into schizophrenia today and the history of antipsychotics and history of schizophrenia.

And Dr. Cummings, welcome to the show. Well, thank you very much. I'm glad to be back and indeed ready to talk about how antipsychotics came into existence and what has evolved since their introduction. the beginning point actually goes all the way back to around 1933. In France, there was a push to develop antihistamines as treatments, and that led to a line of research that ultimately, by 1947, led to the introduction of promethazine,

which produced sedation and calmness in animal models, was not very highly effective in people, but did lead to the thought that it might provide a preoperative way to calm people down. That in turn, however, led to Paul Serpentier in 1950, looking at derivatives, other phenothysine derivatives of promethazine, and one of those turned out to be chloropromazine. It was initially tried in a surgical military hospital in France by Dr. Henry Labarette. It was successful in making people calm prior to surgery and making them somewhat indifferent to the impending surgery.

They tried it in a psychiatrist, volunteer, Dr. Corti, who indeed, reported it had favorable effects until he stood up and promptly fainted. And that was pretty much the end of the drug as a preoperative drug because it essentially turned out to be too effective as an alpha adrenergic antagonist in lowering blood pressure. A friend of Dr. Labrots via a family connection, however, led to you. to its introduction into psychiatry via Dr. Pierre Denacher. He was interested in the calming effect of the drug. He and Dr. DeLay, who was the superintendent at St. Anne's Hospital in Paris,

said, well, why don't we try this in our psychotic agitated patients, and at least we can make them calmer? Because in those days, the treatments were fairly limited. You had electroconvulsive therapy, hydrotherapy, and insulin, coma, none of which were especially antipsychotic in nature. They tried it in 38 patients in 1952, and to their surprise, found out not only did it make people calm or it also made them less psychotic in terms of positive psychotic symptoms, things like hallucinations, delusional thinking, psychomotor agitation. It was impressive enough that

Denneker began giving talks about the drug, and indeed one of the talks he gave was at a conference in Montreal, which got the drug introduced to North America. And in 1955, subsequently, it was approved in the U.S., and as they often say, the rest is history. Chloropromazine spread worldwide and led to, for both good and ill, deinstitutionalization. of a lot of psychotic patients and the development of a whole host of other antipsychotic medications.

Tell me more about the deinstitutionalization. Was that just because they no longer were psychotic and they could live kind of on their own? Or was that a government force to sort of decrease costs? It was both. I mean, in many ways, as chlorpromazine and later the other first generation antipsychotics became the first effective treatment for psychosis.

And indeed, many people were able to be discharged and to live in the community. Frankly, the governments who had been funding large asylums saw an opportunity to decrease their financial burden, which led to deinstitutionalization. Unfortunately, the portion of deinstitutionalization that failed was that these same governments essentially did not create adequate resources in the community to provide ongoing care for the deinstitutionalized patients so that many of them just wound up then, as now, just being dumped onto the street without any adequate follow-up or support. Yeah. Do you currently see our homeless population still with higher rates of schizophrenia and psychosis? The last survey I read about Los Angeles, well, first, California in general, is estimated to have 357,000 homeless individuals. Of those, it's estimated that somewhere between 40 and 60 percent suffer from a mental disorder.

with certainly schizophrenia spectrum disorder being highly represented in that number. I remember being at the APA, the American Psychological Association or psychiatric association in San Francisco a couple years ago. And right outside our lecture was what seemed to be a psychotic individual yelling, all sorts of things. And it just, to me, had some irony. You know, we're a group of about 200 psychiatrists in a room learning about something. something psychiatry related and there's a homeless person still out there and it's it's sad.

It's sad how much suffering there is going on. Yeah, unfortunately, the resources are still very much out of balance. You know, I work at a state hospital. In round numbers, the state is spending roughly $200,000 a year to care for people committed to state hospitals per person. many of the people we discharge, however, are placed in community settings where the degree of financial support for their care

is vanishingly small. And consequently, while they get better and they become stable in the state hospital, many of them subsequently undergo relapse and readmission simply because there aren't adequate treatment resources. Yeah. Well, where do you want to go from there?

I mean, so what's the... Well, let's continue in the history of... Yeah, we can talk a bit more about the history of the antipsychotics. As you might guess, when chloropomazin became a worldwide success, many pharmaceutical firms wanted to own something, similar. So there was something of an explosion of development of antipsychotic medications. And at fact, at one point in the 1960s, the U.S. Food and Drug Administration basically said, we're not approving anything else unless you can prove it's better than chloropromazine

and haloperidol, because they were getting a bit concerned about the multitude of antipsychotic medications on the market. All of the first-generation antipsychotics in some ways are the same in that their antipsychotic effect is essentially due to their ability to block dopamine D2 receptors in the brain. And in fact, in repeated studies, dopamine antagonism counts for about 92 to 93 percent of the variance in terms of their efficacy, meaning there's not much more to be found other than dopamine antagonism. And indeed, that led to the dopamine hypothesis of psychosis, which in its

early days was very simplistic. The thought was simply, oh, you have too much dopamine, and that's why you're psychotic. We have discovered since then that the pathophysiology of schizophrenia and other psychoses is much more. complex. And indeed the first second generation antipsychotic discovered was actually synthesized

by Eichenberger and Schmutz only eight years after chlorpromazine in 1958. This was clozepine. Which was

created essentially because two other anadine antipsychotics had been successful. Loxetane, loxapine, generic name, and prolapine, which was a European drug not introduced in the U.S., when they synthesized clozapine, however, they initially thought it was a failure because the way they tested for antipsychotics in those days

was to give the compound, whatever the candidate was, to the typical white lab mouse, mice are incredibly prone to dystonia. So if it was a potential antipsychotic that blocked dopamine, you got a stiff mouse, kind of starched-looking mouse. When you give clozapine to a mouse, all that happens is the mouse tends to get sleepy and crawls off in the corner and goes to sleep.

So they said, nah, big deal. So the dopamine blockers, the D2 blockers, caused stiffness because of the, because not only does, you know, dopamine block sort of the positive symptoms of, or blocking dopamine block the positive symptoms of schizophrenia and psychosis, but also kind of the movements, right, which is like Parkinson's people have too little dopamine.

Yes. Yeah, indeed the, all of the first generation, antipsychotics block dopamine in the basal ganglia, which causes the extraparaminal symptoms, things like acute dystonia, acetygia, Parkinsonism. They block D2 receptors in the pituitary, which causes elevation of prolactin. And they block dopamine receptors in the frontal lobe, which actually causes not uncommonly some worsening of negative and cognitive symptoms. And some of my patients who need to be on these medications, and you know you start how'd all,

and all of a sudden their face, it doesn't emotionally react as much. Yes. And they seem a little bit more, you know, stoic. Yeah, they developed not uncommonly masked facies, which is, of course, also a symptom of Parkinson's disease. And by the same mechanism, you're decreasing dopamine signaling

in the basal ganglia and consequently the person has less muscle movement including in the face. So coming back to Clozapine, something was different. Something was different. It turns out Clozapine is a very poor antagonist of dopamine

even at fairly robust plasma concentrations. It blocks only 30 to 40% of dopamine receptors. As it turns out, It promotes the release of glutamate, which is the brain's primary activating neurotransmitter. It does that indirectly by binding to an allosteric site for glycine on the NMDA receptor. The upshot of that is that increasing glutamate activity increases activity. in the frontal lobe, but also suppresses dopamine release in the mesolimbic circuit.

Glutamate and dopamine are kind of in a reciprocal relationship with each other. In the early days, there were some small studies in the 1960s looking at clozapine, and people indeed began to notice that patients who did not respond to what were then the dominant first-generation drugs, haloperidol, and chloropomazine did show a positive response to clozepine. Even better, not only did the positive psychotic symptoms respond, often the negative and cognitive symptoms responded as well. Not a surprise given that glutamate activates the person's frontal lobe.

That led ultimately to the drug's introduction, first in Austria in 1972 and then 1974. in Germany. And frankly, had things gone well, it's likely that Clozapine would have replaced all of the first-generation

antipsychotics fairly quickly. It was clearly more effective. To a very large extent, 40 to 60% of people who don't respond to a first-generation antipsychotic will respond to Clozapine. Yeah.

However, six people in Finland up and died in 1975 due to agranulocytosis. And indeed, at that point, people realize that clozapine can cause the body to form antibodies against the bone marrow cells that make neutrophils, granulocytes, and can essentially shut down the person's immune system. Yeah, without neutrophils, you're prone to infections. you're prone to, you know, neutrophilic fever and all sorts of issues.

And it's just harder to fight off foreign invaders. Indeed, most of the people who die of agranulocytosis are actually usually killed by the bacteria that we all live with all the time. But we live in a kind of state of truce with them. But if we have no immune system, those very same bacteria have become invasive. There's, I think, I read 10 times as many bacteria in our body as normal human cells,

like in our gut and on our skin and all over. Oh, yes. We are in some ways, if you simply counted by numbers, there are more of them than of us by a huge factor. So that, you know, tragedy, right? Like, we have a great medication, but there's this significant side effect. and it's difficult to prescribe. It's difficult outpatient to prescribe close apine.

It takes a lot of time because you have to monitor their, you know, neutrophil count closely. I think what you start out weekly, then go every two weeks and then every four weeks. Yes, you start out weekly for six months, and if there are no hematologic abnormalities that are relevant, that's then every two weeks for another six months, and then after a year it becomes monthly. In some ways, it's unfortunate that the FDA didn't go quite as far as the Europeans did in that regard.

In Europe, it's every week for six months, then every two weeks, and then nothing. Does the risk go down completely after a year? The risk goes down substantially. Because this is, if you will, an autoimmune response, the risk, of course, starts at zero before you're ever exposed, it peaks at about four months of exposure at about 1.3%. By the time you're out to a year, it's down to about 0.38%. By the time you're out to two years, it's down to about 6 per 10,000 or 0.06%. So the risk does decline over time. It never declines all the way to zero. But the Europeans reasons essentially that once it's at a very low risk level, warning the person that if they

have any persisting signs of infection, they should go get a CBC may be as good as routine monitoring. Because frankly, at a testing interval of once a month, the odds that you would actually take the sample at the right time to catch declining neutrophil counts is pretty small. So that in some ways, what we're doing in the U.S. doesn't make a lot of sense because the odds are you wouldn't take the sample at the right time anyway. Yeah. Currently, I have three patients on this, you know, out of a full practice, out of all the schizophrenic patients I've had. And one in particular is doing really, really well. Going through college, getting straight A's. He was homeless. He was on the streets, and he's doing really, really well.

Well, and that's very much consistent with clozapine's history. The reason people didn't give up on it, of course, was because of the superior clinical response. In particular, the improvement in negative and cognitive symptoms, the first generation drugs, certainly they improve cognition in the sense that if your thinking is highly disorganized and you're actively paying attention to things that you're hallucinating, then controlling the positive symptoms will improve your overall functioning. But they actually are somewhat negative in terms of their effect on the frontal lobe. And clozapine, in contrast, wakes up the frontal lobe.

The person's more able to think, more able to perform normally on an intellectual level, when Clozapine was first introduced, people were writing things about Clozapine awakenings. Because just as in your patient, they had people who had been dysfunctional for years or decades. And suddenly they were much more normal. You see that at Patton probably because, you know, once they get here, they, you know, they haven't had consistent care. And finally, they get some consistency. I imagine. They do.

And indeed, you know, clozapine in California state hospitals has a usage rate of around between 15 and 20% of our patients are on clozapine. In New York state, it's 53%. And in large part, that's because in schizophrenia spectrum illness, which is what we mostly have in our hospitals, the response rate to drugs other than clozapine is pretty miserable. Yeah. The, you know, 40 to 60 percent for chlozapine, very high plasma concentration olanzapine,

which you can think of as sort of clozapine light in this context. We'll get you about a 9% response rate. Everything else is between 5% and 0. For the severely... For the severely psychotic, mentally ill. More formally, if they meet what are called Kane criteria, this is after John Kane, who really promoted the introduction of Closopine in the U.S.,

if someone has failed two clearly adequate trials of antipsychotic treatment, then the odds that they're going to respond to anything other than, and chlozapine is pretty low. That's the formal definition of somebody being refractory. And how long is an adequate trial of a different medication? Minimum of six weeks. Six weeks, okay. And also has to be at a therapeutic plasma concentration.

Okay. A lot of, one of the, in treating this severely mentally ill, one of the common mistakes clinicians make is to go by dosage. as to whether the person's receiving enough medication, dosage is only weakly correlated with plasma concentration because the metabolism of these drugs is so variable. So measuring plasma concentration to be sure there's actually a therapeutic amount on board becomes a very important issue in being sure that somebody

who's treatment-resistant or refractory is actually receiving. adequate treatment. So can you get aceshesia on clausoro? You can, although it is very rare. In fact, all of the extra paramil syndromes are pretty rare with clozapine because it is such a poor dopamine antagonist. I think it might be worth it to go over aceshesia because I think it's very important to be able to catch it early on. And I think especially since, you know, people outside of psychiatry,

practicing, maybe even therapists, I think that's one of the things that, you know, you should, if you see this, you should call the psychiatrist, you know, get a hold of them, send them, get them help. Because it's miserable. It is miserable. You know, acute dystonia, which is an acute muscle contraction is painful. But it's not nearly as miserable as they, Acethesia, Parkinsonism, that is having decreased movement, bradycanesia, muscle, stiffness, is not a great syndrome, but it usually doesn't make people out absolutely miserable. In contrast to that, acathesia actually produces suicide in some individuals because it's such a miserable condition.

One of my more eloquent schizophrenic patients who had had acethesia described it as feeling like you have ants crawling up and down the bones of your legs. It is characterized by both an internal sense of anxiety and a near irresistible urge to move, especially the lower extremities because the muscles, while they're not cramping, they feel uncomfortable. They feel like moving will help alleviate that discomfort. Yeah.

So it's like, do you feel internally red? restless. Do you feel like you need to move? Yes. As you're watching them, are they moving a little bit more? Yes. Okay. They may have aceshesia. They may have. And indeed, there is a, the most common instrument used to measure acethesia is the Barnes' acathia rating scale. And it looks at three factors. It looks at, indeed, the objective movement is the person moving. Can they not sit still? What's their internal sense? of restlessness and anxiety. And then third factor is how much are they distressed by these feelings?

When I was at an APA, at forensic talk, they talked about things you may be sued for. And this is one of them, like, you know, discharging a patient from the hospital with ecsthesia. You know, on discharge note, patient restless, patient, you know, you know, moving, jittery, and in the subjective there may be something like patient says they're anxious, patient says they want to move around, and it wasn't addressed, and then they get discharged, and then if they hurt themselves or someone else, that could be a really tough malpractice case against you. Yes, indeed, odds are you'll be settling in that case. the underlying pathophysiology of acethesia is a little more complicated than the other

extra-paraminal syndromes. Dstonias and Parkinsonism are pretty much too little dopamine in the basal ganglia compared to the amount of acetylcholine input to the basal ganglia, which is why the anticholinergic are effective in treating both dystonia and Parkinsonism. In contrast, the underlying pathophysiology for acethesia involves not only dopamine and acetylcholine, it also involves norapinephrine and serotonin inputs to the basal ganglia. And unfortunately, that makes it often a difficult syndrome to treat success. Certainly choosing a less robust dopamine antagonist is one treatment and often the place to begin if the person can do well on a lower dose

Or you can always of course consider switching to clozapine or to a less robust dopamine antagonist like quatyapine You can also try treating with amantadine which increases dopamine release in the basal gasealase ganglia. What about, usually my go-to is, one, can I decrease the dose? Two, consider something like propanol. And then three, like clonopin. Any thoughts? Yeah, the benzodiazepines by increasing GABA, which is the brain's major inhibitory

neurotransmitter, will work in many cases of acetheia. The beta blockers have been the first line treatment historically. Interestingly, a head-to-head trial of propranolol versus mertazepine antidepressant actually found the mertazepine to be more effective. Wow. The propranolol was effective over a five-day course in 30% of the patients exposed. This was propranol versus mertasapine versus placebo. the myrtazepine at 15 milligrams at bedtime was effective in 43% of the cases. The placebo was effective in, as you might guess, 7% or a much lower percentage.

Yeah, it's hard for a placebo to work on this one. Okay, so you were saying amantadine. Yes. Amantadine has been underappreciated in terms of treating extraparamidal. symptoms. It's been a unique drug in the sense that it was developed, of course, to inhibit influenza A, which it's almost never used for anymore. It turns out it's effective in treating as a good routine treatment for extraparaminal symptoms. It's also effective, albeit not very robustly in treating tardive dyskinesia. 15% of TD patients will respond to amantadine.

And acathesia in particular appears to be responsive in those people who can't quite get to a lesser dopamine antagonism. Not as effective as either the beta blockers are mertazepine, but it's certainly something additional to consider in the armamentarium. The nice thing compared to the anticholinergic medications is that amantadine is not anticholinergic, and it avoids all the problems with, decreased memory consolidation, blurred vision, decreased GI functioning, urinary retention, all of the anticholinergic problems that people can run into. That makes a lot of sense, because those are some of the, you know, most difficult, difficult side effects to sort of cope with long term is, of course, decreased sensorium, decreased ability to focus and concentrate, and so on.

Okay, what do you think about, I read one article about aceshesia, induced homicide. That has occurred. As you might guess, some people who feel chronically restless and miserable, depending on the other elements of their pathology, may also become irritable, aggressive, violent. Is that something like in the particular paper, I think it was out of Australia, like a forensic hospital? They looked at the P450s and the you know, the concentration of the medications, which was a lot higher than expected in the individuals that had the aceshesia and had these pretty bad events that happened. It kind of, it kind of, it's a scary thing to think about that this could happen.

It is, and it's another argument for not making the assumption that because you're giving a drug at a standard dose, that the plasma concentration is what you would expect. If the person is a slow metabolizer of that particular drug, or if they're taking another drug that inhibits the enzyme that metabolizes that drug, their plasma concentration may be a lot higher than they either need or then you as their clinician expect, and that may be the reason for their adverse effects, as you can tell them, a big advocate for actually measuring plasma concentrations. And two of the contexts in which you should always measure a plasma concentration is if you're giving a drug at what you think is a therapeutic dose and you're not seeing anything,

no benefit, no side effects, you may be looking at a rapid metabolizer. None of the drugs actually getting to their brain. Conversely, if you're giving somebody a drug and they're getting horrible side effects at what you think is, oh, that's just an average, moderate dose, measuring their plasma concentration may reveal that you're actually giving them a super therapeutic or in some cases a toxic dose of the drug. Along with this handout that you've written, I like to, do you have like a table of like normal doses for the medications, like what the normal therapeutic ranges that I could give to the people who listen to this? Yes. One of the chapters that, again, the group that I work with has compiled is a, it's actually a policy.

chapter for the state on expected or therapeutic plasma concentration ranges for antipsychotics, the ones that we most commonly use, and mood stabilizers. Okay, so we'll try to get that into the resource library for people who want to follow the show notes. Yes, I can send you a copy of that. Okay, wow. So aceshesia, antipsychotics, any other medications outside of the antipsychotics that people need to worry about for aceshesia.

Yes, any drug that lowers dopamine signal transduction can cause acethesia. That includes the SSRI antidepressants. If you increase brain serotonin, the dopamine neurons that project into the basal ganglia have serotonin receptors on their surface, 5HT2A receptors, that if those are, you're, are stimulated, it turns down the amount of dopamine released. So those can cause everything from acetheia to in very rare cases, tardide dyskinesia. Also, any of the, some of the anti-emetic drugs, also, even though they're being used to decrease nausea, some of those are dopamine antagonists, drugs like compasine.

and they can cause all of the same extra-paraminal symptoms that the antipsychotics can. So what do you, I want to move into like Abilify, and kind of the unique aspects of Abilify, Arupipersol. Yeah, well, indeed, there are, people now classify the antipsychotics into three groups, not very cleverly sometimes called the first-generation drugs, which we've talked about. Second generation, which are the clozapine, olanzapine, quatiopine, respiradone and related drugs,

still largely dopamine antagonists, but with some additional features. And then finally, what have been termed the third generation antipsychotics, which are the partial dopamine agonists, and those include aeropiprosol, Brexperazol, and cariprazine. These drugs all share some things in common. They have a very high affinity for dopamine receptors.

In fact, higher than either the first or second generation drugs, which means if they're present at therapeutic concentrations, the first and second generation drugs aren't going to be seeing a lot in terms of dopamine receptors. they all lock dopamine signaling at about 25% of dopamine's maximum signal transduction, which means they tend to produce kind of an all-or-nothing response in terms of treating psychosis. They, if 25% happens to be about right for this person's signaling in their brain, You get a great response.

If it doesn't happen to be right for that person, you tend to get a not-very-good therapeutic response. You don't have much ability to vary where that signal transduction is locked because of the very high affinity of these drugs. The nice thing about all three of them is that their side-effect profiles is very favorable. They are largely metabolically neutral. that is unlike drugs like chlozapine and olanzapine,

they don't tend to make people gain weight or to induce glucose intolerance or lipid abnormalities. They don't have much in the way of affinity for alpha receptors or histamine receptors so they're not very sedating. They don't lower blood pressure

so that when you get a great response, you've got a pretty clean drug. The trick is always of course in identifying those people who are for whom that degree of dopamine signaling happens to be right for their brain i think more and more i've seen like abelify used for issues outside of like schizophrenia um any thoughts on like it's used for bipolar or it's used for major depression uh yes well in in that context some of the second generation drugs like um Rospadone and olanzapine have exhibited mood-stabilizing and antidepressant properties as well as antipsychotic properties.

The third-generation drugs also tend to be able to improve mood, most often serving as an adjunctive medication in major depression and also exert mood-stabilizing properties so that they can be used as mood stabilizers as well as antipsychotics. In part that's driven by the quality of the molecules themselves, and also it's been driven by the desire of pharmaceutical companies to broaden their market. Because, of course, the number of people with schizophrenia is finite. Worldwide, it's about 1% of the population. In contrast to that 6 to 8% to...

of the population will have an episode of major depression. Bipolar illness may range up to 2 to 3% of the population if you count all of the variants of bipolar illness. So there's a broader market out there that has been of interest to the pharmaceutical firms. It seems to me that when someone's in a very strong dissociative state, and maybe they've been there for a couple days, like someone who suffers from, you know, borderline personality disorder, and they've been in this sort of dissociative place for maybe even weeks

before I see them. An antipsychotic, you know, like Risperdol, three days later, they're out of that dissociative space. Yeah. And that makes a lot of sense in that, you know, I think one of the things that the ICD10 got right is they renamed Borderline Personality Disorderline. Instead of that, they've labeled it, I think, more correctly as an affective discontrolled disorder.

These are people who have very intense limbic or emotional responses to things in their environment, usually relations with other people. And that appears to be the underlying basis of the disorder. So if you can stabilize the functioning of their limbic system, that goes a long way toward undercutting the pathology of the disorder. I think, well, at least I'm hopeful that in the future we may reclassify this from being a personality disorder more to being a mood disorder, because I think that more appropriately is where it fits.

The term borderline personality disorder is kind of a misnomer altogether, and that it was originally named that because these persons were... thought to be bordering on schizophrenia. That turns out not to be the case. They don't become schizophrenic. They may have micro-psychotic episodes or dissociative episodes related to affective intensity, but they're not schizophrenic patients.

The border between neurosis and psychosis, right? Yes. Yeah, you know, I think it's a more, it's useful to be able to diagnose someone with this rather than misdiagnosing them with like bipolar or schizophrenia, because I think it has a lot more hope, because there are studies that show that within five, seven years after treatment, usually pretty intensive psychotherapy, either DBT or mentalization-based therapy

or transfer and focus therapy, there can be a resolution of the diagnosis in mentalization-based therapy in about 70, 80% of the population no longer meet criteria. Yes, and indeed, when they've done long-term studies of people who were diagnosed in their younger years, usually in their 20s with borderline personality disorder, when they've gone and looked at those populations much later in life, 40s, 50s, the vast majority of them no longer meet the diagnostic criteria for borderline personality disorder, which I think also speaks to the issue that this is. isn't so much an issue of personality as it is an issue of a dysfunctional limbic system. Well, I want to make sure we covered everything you wanted to cover about schizophrenia. So is there any sort of final thoughts or things you want to talk about? Yeah, I think probably in terms of looking to the future, we've talked about the antipsychotics.

And certainly they were a major advance. over no effective treatment at all. But we still are a long way from being able to really return people to wellness, even with drugs like chlozapine. Only about 6% of the schizophrenic population are able to live independently, work, have successful relationships. And in part that's because we're treating an illness that starts in utero, and we're often not starting treatment until the person's in their teens or 20s.

I think if we can reach the point where we can identify who is at risk, using some of the same modulatory properties of the antipsychotics, but at lower doses, there is hopeful data out there that we may actually be able to prevent the development of schizophrenia. In any ways, schizophrenia is a developmental, dementia in which there is loss of connection between nerve cells and actually a loss of nerve cells. If we could prevent those losses, we may be able to prevent the illness.

And we go into more details on that actually in our prior talk on schizophrenia. Yes. In relation to kind of like, you know, how to best potentially solve or help this population. If we could early identify them and then treat them, you know, potentially that could make a huge difference. It can because, you know, currently, certainly even with our best drugs and our best treatments, our effectiveness in treating schizophrenia is still pretty limited. Yeah.

Sobering. Well, Dr. Cummings, it's been a pleasure to have you on once again. Okay. Yeah. if you found this helpful, jump over through the links and the show notes to the corresponding resources. And hopefully that's helpful. Let us know. And until next time, thank you, Dr. Cummings. Okay, thanks.