Pod Insights Psychiatry & Psychotherapy Podcast Psychiatrist Effect in First-Episode Psychosis: HAMLETT Study, Antipsychotic Tapering, Dopamine Supersensitivity & Sex Differences with Franciska de Beer About this episode In this episode, Dr. Puder sits down with Franciska de Beer, MSc, first author of landmark HAMLETT-OPHELIA Consortium papers in JAMA Psychiatry, World Psychiatry, and Psychological Medicine. They dive deep into the psychiatrist effect in first-episode psychosis, revealing that individual psychiatrists explain approximately 10% of variance in positive symptom improvement and daily functioning, even after controlling for medication dose. The conversation explores groundbreaking HAMLETT findings on early antipsychotic tapering versus maintenance, dopamine supersensitivity after high-affinity D2 blockers, sex differences in treatment outcomes and clozapine levels during menopause, and why shared decision-making and reflective functioning matter more than ever in psychosis care.
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Link to blog https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-263-psychiatrist-effect-in-first-episode-psychosis-hamlett-study-antipsychotic-tapering-dopamine-supersensitivity-amp-sex-differences-with-franciska-de-beer
Link to YouTube video https://youtu.be/B_QLIIglJ9k
Transcript 10,677 words · 2 speakers
Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.
0:14 David Puder? All right. Welcome back to the podcast today. I'm thrilled to be speaking with Francesca De Beer. She is a talented researcher, soon to finish her PhD at the Center for Clinical Neuroscience and Cognition at the University Medical Center Groningen in Netherlands. Francesca is the first author of multiple groundbreaking articles from the Hamlet-Thella Consortium, including key publications in JAMA Psychiatry, World Psychiatry, Psychological Medicine, Schizophrenia Research. I first reached out to her after stumbling upon her article that she first authored called
0:54 David Puder? "Psychiatrist Effect on Positive Symptom Severity and Daily Functioning During Psychotherapy for First Episode Psychosis Patients." Many of you will know, I often cite McKay's study on psychiatrist effect in depression, one of the only psychiatrist effect studies, so I was overjoyed to find a second study that looked at psychosis and the psychiatrist effect. I've since learned more about her research interests and have been intrigued by her work on first episode psychosis, and I think there's a kind of a new question of when we should continue antipsychotics, when we should not continue antipsychotics.
1:39 David Puder? And so hopefully, we'll have some of the new research on that discussed in this episode. So, welcome to the podcast.
1:46 Speaker 01 Thank you for having me.
1:49 David Puder? So, maybe we could start with a paper on psychiatrist effect and go from there. So, do you want to describe the basic findings of this research?
2:01 Speaker 01 Yeah, sure. I love your introduction and I think the McKay article, you you love, I love it so much as well. So I think one of the main issues when we talk about psychiatry is that offshore, we want to improve patients' recovery, right? And the main way we go about it is look, okay, how can we address patient characteristics? Like their economic well-being, like their social functioning. We tend, I think, to overlook that there is someone else across the table that also has an influence in these patients' outcomes, namely the psychiatrists.
2:44 Speaker 01 And I think there is some literature, or there is some decent literature about psychotherapy and the effect of a therapist in psychotherapy. But the person also matters, the clinician matters, when there is drugs prescribed in pharmaceutical and pharmacological therapies. And that is what we wanted to address. What is the effect of the psychiatrist when patients were recovered from asphericosis in their treatment outcomes?
3:15 David Puder? Beautiful.
3:16 Speaker 01 Yeah, so what we did is, we have a nationwide study, the Hamlet study, that has about three hundred and fifty patients, well, we used slightly less of them, from many different psychiatrists. And that allowed us to have eighteen psychiatrists with an average eleven patients per psychiatrist. And so we could see, okay, does the patient's outcome of a, over a period of twelve months, so of one year, depend on the psychiatrist? And we indeed saw that that was the case. So we found that the psychiatrist could explain about ten percent of the patient's outcome after one year, which is quite a decent amount.
4:01 Speaker 01 And what was quite interesting is that it's not only about the psychiatrists themselves, but also about how they prescribe medication, because we saw a significant interaction effect with the drugs they prescribed. And I think that is the new value of this study. We not only show that it's the psychiatrists, but also the way psychiatrists prescribe medication, that matter.
4:25 David Puder? So the basic group of people, these were people that had first episode psychosis and then they were stable, right? They had low scores on their psychosis scale. And so these were either randomized to be tapered, or to stop the antipsychotic medication, or to continue the antipsychotic, right?
4:49 Speaker 01 Exactly, exactly, yeah. So during this study period of 12 months, they were initially randomized to either reduce antipsychotic medication or continue it for a period up to one year after remission. But in this study, our follow-up period extends that. So we started to follow them when they were half a year in their remission. So we had the trial phase, and we also have the phase afterwards, which gives us basically two views. One, a psychiatrist aiming to maintain a patient on either the treatment arm, and the phase afterwards where psychiatrists were free on either reducing or increasing,
5:34 Speaker 01 well, increasing always, but reducing the dose or not to.
5:39 David Puder? Great. So I've actually done a presentation on psychiatrist effect, reflective function, therapist effect. And I'm going to pull up one of my slides, maybe you can explain it. It's figure one from the paper. For those of you who are on YouTube, you can see this. So we'll try to describe it for those listening. So describe for the for the audience what what we're seeing here in terms of psychosis severity change scores based on different psychiatrists.
6:10 Speaker 01 Yeah. So what we see here is a bar plot where we see one bar per psychiatrist. And what's plotted on the Y axis is, does a patient improve or worsen in their amount of psychotic symptoms? So what we did is we measured symptoms of variety with the PONS, the positive and negative syndrome scale, the positive item skills, so how many delusions do you have? How many hallucinations do you experience on a daily basis? And well, a researcher rates this kill. We did this shortly after they were in remission, so three to six months, and we did it again after one year.
6:51 Speaker 01 And basically, what we do is how does one improve or worsen over the period of a year? And we averaged those what improvements and decreases over all patients of a certain psychiatrist. So psychiatrists had an average eleven patients, so you have an average of eleven patients. And what we see here is that some psychiatrists show a marked, well, a slight worsening, but not too different from uh from zero, so basically the patients remain quite stable. Then there are also some bars indicating that some psychiatrists, they actually show quite a marked improvement over the course of a year.
7:34 Speaker 01 And I think this bar plot actually shows what indicates that while some psychiatrists, some patients with some psychiatrists, they have markedly improved outcomes compared to patients from other psychiatrists.
7:48 David Puder? Um hum.
7:49 Speaker 01 And this may be a bit controversial to say, but there is the belief that while there are some clinicians that may be more effective than others. Some literature suggests it's maybe fifteen to twenty percent of psychiatrists uh well, having better outcomes and fifteen to twenty maybe worse outcomes. I'm not sure about the percentages, but I do think that intuitively, yeah, it makes sense that if some psychiatrists may be more efficient in giving therapy than someone else. And this bar plot, I think, quite effectively shows that.
8:27 David Puder? The variance explained by psychiatrists was 9.1%. And the variance explained after controlling for antipsychotic dose was 9%, which was interesting to me. Like, the dose didn't change that some psychiatrists did a great job, meaning that it's not purely dose-related, that some psychiatrists did better than other psychiatrists.
8:52 Speaker 01 Exactly. And I think the personal skills of psychiatrists, the communication skills are of massive importance. And like Hannah mentioned, especially with psychosis patients, where there, well, there may be a tendency for paranoia. I mean, especially when someone's not easy to trust anyone. I think it takes quite some dedication and some patience and massive communication skills to build this level of trust. So a patient's really open and able to explain and to be that honest about some symptoms, because it can be so personal and scary to explain. So I think especially with psychosis patients,
9:34 Speaker 01 the psychiatrist act is of major importance.
9:38 David Puder? Yeah. One of the, one of the things I've tried to convey to residents over the years is the amount of energy that we psychiatrists spend on developing those skills, developing our psychotherapy skills, needs to be as important as learning all of the details of neurotransmitters and different medications and side effects and management of those side effects. One thing that was interesting, I'm wondering if we could kind of also mention here, is baseline severity explained 38.6% of the variance in this group. Tell me about that, that amount. It seems, you know, it's about three, four times as much, right? As the, the effect of the psychiatrist.
10:23 David Puder? So baseline severity was very potent in predicting, you know, how well someone was going to do. Tell me about that and what you think about that number.
10:35 Speaker 01 Yeah, so it basically means that how well you recovered initially predicts how well you will do after one year. So if you recovered really well, then the chances are that you'll be doing really well after a year are bigger than when you recovered very poorly. Because then your prognosis is somewhat bleaker.
10:55 David Puder? Um, yeah, and I think, I think that that is, it's a bigger impact than psychiatrist effect, baseline severity effect, like that early response, right? But there still is a psychiatrist effect, which is pronounced, which is also similar to what we see with therapist effect. It's around that nine percent, which is interesting to me. Uh, some things didn't have an effect on all, at all, right? Like the frequency of the psychiatrist contact, medication non-adherence, effective treatment center. How do you make sense of these things?
11:29 Speaker 01 Yeah, so I think the frequency of psychiatrists was overall fairly similar, so I'm not sure.
11:35 David Puder? Okay.
11:36 Speaker 01 Have some, we didn't have massive outliers, I think in the Netherlands, the frequency was fairly consistent overall. So there were no major differences. I can understand that, that was a, that was a contributing factor. And these patients also embedded in a bigger care system where they do not only see psychiatrists, but also nurses and psychologists. And the frequency of seeing a psychologist was important for psychosis severity. So I think one issue that we did not address here, but would be lovely to address in future studies, is that how does the team impact recovery? I mean, what kind of resources do you need for patients' recovery?
12:21 Speaker 01 And also who benefits from what? Because there may be a young male, early twenties, they may need different treatment needs than someone. For instance, a woman being vulnerable to psychotic episodes during perimenopause, where there are also other cosmetic complaints. So yeah, I'd love to be looking at what the best combination would be per person.
12:47 David Puder? That's great, okay. Let's go to the next slide here. So this is the, now we're going to be talking about daily functioning change scores. And so this is like another piece of the variance that they looked at. And they found the variance of this was 10%. So tell me about this.
13:06 Speaker 01 As an next to how many symptoms patients experienced in their daily lives, we also looked at how well they were able to get along with their daily functioning. You can think of how well they were able to communicate with other people during the household calls, whether they will be able to work or not. They rated their own daily functioning. And we saw that when also similar to the psychosis severity, that patients with some psychiatrists showed better improvements. And better improvements in this case means a greater reduction in symptoms severity in daily functioning. And this, yeah, this was 10%, which is quite, quite a lot.
13:50 Speaker 01 And we also saw that there was a significant interaction with those or explaining 4%. And what that means basically is that it doesn't only matter who your psychiatrist is, but it also matters how they prescribe the antipsychotic drugs. And I think here that is this combination of this interpersonal aspect, how much trust is someone being able to build up with the patients? Or how much openness is there about undergoing symptoms? And how well is a psychiatrist able to address these symptoms? For instance, because they emerge very suddenly, or you need different kind of treatments with fewer side effects. So that needs to be a switching or dose adjustment.
14:34 Speaker 01 And I think some psychiatrists may do these adjustments more efficiently than others.
14:41 David Puder? Yeah, so, you know, we think about like, you know, what wasn't measured here. We didn't really measure in this study why some psychiatrists were better than other psychiatrists, which has always been a question of mine. Therapeutic alliance, of course, coming together with the patient, trying to, you know, have consistent goals. What kind of things do you think might have been going on that made one psychiatrist better than another psychiatrist?
15:09 Speaker 01 I think that's a very intriguing, difficult question to address. I think it surely has to do with the ability to build trust because of the tendency of paranoia. Then also, most likely, the degree to which decisions were openly discussed, like the shared decision making.
15:30 Speaker 01 And I think the process of shared decision making is crucial. And for instance, if talking, when talking about medication adherence, I think it's so important that both parties are on the same page when a drug is prescribed and even basically to choose which drug you want to choose. That should be ideally, if, whenever possible, of course, I understand there may be cases that's not possible, whenever possible, this should be an open conversation.
16:02 David Puder? Yeah, I think, I think it's, a lot of the issues that I run in my own private practice are things like anosinemia, like where the patient has no insight into their illness. This, this can create increased difficulty in even getting the patient to agree to take a medication. Sometimes I've started a kind of a new, new approach with just doing pure psychotherapy without medication for the first couple of months, just because the patient's refusing medication, but maybe not so flagrantly psychotic, but not to the point where it's, they're easily hospitalized or, you know, put in a hospital, injected with an antipsychotic or something.
16:45 David Puder? But yeah, any other thoughts on like, what insights this can give us as psychiatrists for what we could do to improve our ability as psychiatrists?
16:56 Speaker 01 I think the honest insight is is a very, very good one because where do we start if someone is not willing? And I think this is an extremely difficult, difficult one, but important one to to address before starting well, LIIs or perhaps more admitting someone to a hospital. So I like your approach very much on first trying psychotherapy in the first case.
17:25 David Puder? How how is it in the the Netherlands? Like, what what is the approach for first episode psychosis? Like, what what normally happens to a patient? Are they admitted to the psychiatric hospital? Are they started on medications in the psychiatric hospital? Or they started outpatient?
17:41 Speaker 01 That fits greatly on whether or not hospitalization is necessary. So in many cases, there is a hospitalization. And in those cases, there are often antipsychotics prescribed. Say, ten milligrams of lenzepine is extremely common for patients to receive. I think that's the most common way. Also, in outpatient clinics, therapies are started typically, again, medication with some psychotherapy. I think those would be the most common routes. And it depends on whether someone was, whether the psychosis derailed a lot, so hospitalization
18:20 Speaker 01 was necessary, or the person and the environment interfered in time for to go to a regular GP and start antipsychotics, either there or with a specialized psychiatrist.
18:32 David Puder? I've heard about in Amsterdam, the rates of high use of high potent THC. Is this play a factor in in how you determine, you know, if you're going to try to take someone off of an antipsychotic or not? Have you? Has there been any thought on that?
18:51 Speaker 01 Well, I think that implicit that was the assumption that when someone has a drug induced psychosis and the person has really stopped using the antipsychotics. They may be the well better suited persons to taper off antipsychotics. And interestingly, very, very recently, I have done a study on what happens after people stop antipsychotics. So patients tapered off their drugs, not all of them, but part of them in the HEMNET study. And when it tapered, some of them actually reached those arrows that are completely discontinued. And I, in those patients, I looked, okay, but if they discontinue, what happens after that stopping point? And I, we followed them up for about four years.
19:38 Speaker 01 And we did a cluster analysis because we were interested, okay, what kind of trajectories do people typically follow when they stop the drugs? And what we found is that there were about two groups who started the antipsychotics fairly quickly again, so say after five months. And one group of these was also hospitalized very easily or quickly. So about after four, five months, a subset of patients, nine percent. I still think nine percent is not too many, but nine percent of the patients who stopped, they needed a hospitalization. And typically, these were male patients with lower education and quite high care needs. So about the double the care needs of other patients compared to others.
20:20 Speaker 01 Then there was also a group of patients who was able to stop medication for a very long time, did not relapse, did not have hospitalization. And those were people who were fairly young, the first psychosis. They had good education, quite high functioning. The highest occupational rates, um, had partners quite often. And what we noticed, what we did not expect at all, was that they had initially quite high drug use. So we think these, a part of these patients who were able to stop medication fairly well with those who had initial drug use, but then most likely stopped drugs or at least way, way less than initially.
21:06 Speaker 01 And those may be the patients that, yeah, could do better without medication.
21:13 David Puder? Okay, that's great, that's good to hear. Let's talk about the JAMA article. This is, I'm just gonna pull this up so people can see what this looks like. It says, "Early dose reduction or discontinuverse maintenance antipsychotics after first psychotic episode remission." So, looks like you were the second author on this, congratulations. This is, I mean, you've done some great articles at such an early time in your career. Talk to us about this study, what was found, the main findings, and things that it kind of adds to our discussion.
21:55 Speaker 01 So, for people's background, what we did is we randomized about 350 people who experienced a psychotic episode for the very first time, so first episode psychosis, and they were randomized to either dose reduced, yeah, no psychotics, faster than guidelines prescribed, so within the first year after remission, or they could have to maintain the dose on which they registered remission for at least one year. And that is because there's quite a debate about what would be best. I mean, can we taper off earlier? We know that it has a risk of increased relapse, but I mean, it may have long-term functional benefits. And in fact, there was a Dutch study that showed that in the long term, after seven
22:39 Speaker 01 years, the group who dose reduced early had long-term functional benefits. And that caused, at least in the Netherlands, quite some opiate with some psychiatrists, dose reducing early, others maintaining to the guidelines more. And with that, there was quite some difference between how psychiatrists dealt with this situation. So there was actually need for a big randomized controlled trial to give some more solid At least in a bigger group evidence.
23:09 David Puder? Um.
23:10 Speaker 01 So what we saw uh after, we we looked, okay, so what then happens after one year after people ha- were in remission? And we saw that those who dose reduced early had a higher risk of relapse compared to those who maintained stable under dose. And also that the dose reduction group had a lower quality of life compared to the maintenance group. And now there's something, I think, is very important to say here, that this is only true for the male patients.
23:43 David Puder? Um.
23:43 Speaker 01 The quality of life reduced in the dose reduction group in male patients, not in the female patients. I think that is fairly interesting and it calls the question of, okay, but were the female patients dosed too high initially then? Or are they better able to dose reduce? I mean, does it have something to do with potentially a larger social groups or tha- that they are more open about their symptoms? So we do not know the exact causes, but I think this is a very relevant finding to to mention here. Now, we also, thi- this was short term, now we were so interested, of course, in what
24:26 Speaker 01 happens in the longer term because we knew that dose reducing early has a greater risk of relapse. And what we saw after three or four years is that patients who dose reduced had better daily functioning compared to those who maintained the dose redu- who maintained that dose. And now what is crucial here is that this is not caused by a lower dose, because at the three and four years, they had fairly similar doses. Actually, there was um. The the dose reduction group even need more slightly higher dose than the maintenance group. So what we see here is that there's functional benefit of early dose reduction.
25:08 Speaker 01 But that is not because of a lower dose, because the doses are the same. So it has to be something different. And I think we come back, maybe touch upon the psychiatrist effect here. So does it, we think that the process of early dose reduction will have benefits. But then what is there about this process that could be beneficial? I mean, is it the educational component? Is it that a patient feels autonomy? Because when someone, a patient and a psychiatrist, they agree on, okay, let's dose reduce, they do this together extremely, extremely slowly. So dose reduction is a process of months.
25:50 Speaker 01 And there is a conversation, ongoing conversations between a psychiatrist and a patient. Okay, how are you feeling? Can we go lower? Should we stabilize? Should we increase? Where the patient may also feel increased autonomy of, okay, I report these symptoms. And now I can also sort of not completely make my own decision, but be involved in this process of medication.
26:15 David Puder? Hmm.
26:15 Speaker 01 Decisions. Also, they experience what happens to them when they lower the dose. I mean, they experience apps that want to lower doses, they have more symptoms and they feel like, okay, but this is then what this drug does to me and it helps me to not hear voices, for instance, and improve or at least keep my job, something. I think that is a learning component as well. And I think that we have a slight backup from literature here because there has been a previous study where, uh. So there have been two previous studies that that have contradicting results. One said, okay, a long term uh early dose reduction is beneficial. And that one was open label.
26:59 Speaker 01 So both patients and psychiatrists knew what was happening. There's also one that was double blinded. So both the psychiatrists and the patients did not know whether there was a reduction or whether there was continuation. And that study, interestingly, did not show a beneficial effect of early dose reduction. And I think what that shows is that this open label process, so both patients and psychiatrists know what is happening and make deliberate decisions. It's crucial for this long term benefit.
27:29 David Puder? Hmm. You know, I'm I'm also thinking about how if if you're a psychiatrist and outpatient, yeah, and this is kind of what you were saying, but maybe I'll just reiterate it one more time. It's like if I if I reduce, if I reduce the dose, and let's say the patient is skeptical that they need to be on this at all, right? So I reduce the dose and they see that some symptoms come back. And it's an it's enough symptoms to let them know that the symptoms are back and they're distressed, but it's not so much that their insight is completely gone, right? Because if you if if all of the medication is taken away, then their insight can be completely gone.
28:11 David Puder? You, as a psychiatrist, are now part of their paranoid structure, maybe. You're trying to poison them. Maybe you're part of the CIA, the FBI, coming after them, you know? Like, so if if all of their insight is stripped away completely, you know, it could be bad. And some patients will stop their meds anyways. But if instead you're a psychiatrist and be like, no, let's like, let's reduce, we're gonna talk, we're gonna see if it's worse, better. And then they come back and they can talk and you then you have more time to gain that rapport as well before they just like quit altogether. Because I've had patients who are like, no, absolutely not, don't want to be on anymore, never want to come back, right? And then struggle.
28:52 Speaker 01 Exactly, yeah.
28:53 David Puder? Yeah.
28:54 Speaker 01 And I think there's a crucial aspect here is that it does really matter that there's good monitoring. So when you dose reduce, there should be really, really regular monitoring. I mean, ideally every week, but. Very, very frequently at least. And this could be done by psychiatrists, but in a lens is also done by nurses and psychologists.
29:15 David Puder? Hmm.
29:15 Speaker 01 So the workload is slightly, well, distributed among people. And I think this is crucial because if you don't have caregivers who know what. I mean, everyone has these relapse symptoms, which are quite personal, like distress, the sleep. Is it hearing voices more often? Is it a specific type of voice? Everyone will have their own landmarks for relapse. And I think having a caregiver that knows them per person and is able to monitor them very frequently. That is crucial because we should not just discontinue or dose reduce without any guidance. I think that's the worst idea ever. So we need to be able to provide the very good monitoring.
29:57 David Puder? Yeah. Yeah. Very good. Okay. And then there was a letter that you guys did that was kind of like commenting maybe on someone else's critique of the study or something. I'm curious, I'm just going to pull that up to show you what I'm, what I'm talking about. But what, what came from this letter? What I was thinking about it was we, you really differentiate between three types of antipsychotics and how they may differentiate in the long-term outcome of someone who's coming off of it like. And this, you know, like if they're on a strong dopamine blocker like Haldol or Spironolone versus a weak D two antagonist like
30:40 David Puder? olanzapine, quetiapine, or a partial D two agonist like arperbazole. So tell me about how these different medications differ when we are trying to bring someone off. And you have more about the study, I guess, the Hamlet study that you guys were doing.
31:01 Speaker 01 I think for a very long time, people have sort of assumed that it's important what dose you prescribe and that when you taper off an aniacotic, it doesn't really matter what type of aniacotic it is, but you're more into, okay, how much dosage is it? And then the dosage, yeah, would be sort of similar among all aniacotics. But when you think about it, aniacotics work differently on the dopamine system. There are quite some differences. There are these antagonists, right? They bind to dopamine D two receptors and they actively antagonize, so they inhibit the dopamine signaling on that receptor.
31:43 Speaker 01 And you have aniacotics in the antagonists who do this very heavily, so they bind very tightly and they block a lot. We call these the high dopamine D two affinity antagonists. Any like haroparidol and risperidone. And there are aniacotics, yeah, they also bind, but less tightly and but if they bind, they inhibit. These are lenzopine and cattipine. We only have one clozapine. So we we categorize clozapine as in this group too, but we only had very, very few cases of clozapine use in the Hammond study because, well, these were remitted patients and typically in the Netherlands, you give clozapine to treatment resistance. And then there's a different group of aniacotics that, well, they bind with very high affinity
32:28 Speaker 01 to dopamine receptors, meaning that you need a small dose to bind to many of the dopamine receptors in the brain. But when they bind, that is antagonism, meaning that's stimulation, partial stimulation. So they're stimulation, but less than a dopamine stimulator receptor. So meaning that in the end, you have a reduction of your dopamine signaling. Because aniacotics, they all reduce dopamine signaling in one way or another. So that gives us with the three types of anisocortic drugs. And what we were interested in, okay, but does it matter if we take, when we taper, what kind of drug we are tapering? Because on one hand, there's this view that, okay, the speed by which you taper is really important.
33:13 Speaker 01 And if you taper really fast, then that will be the, give you the highest risk of relapse. And we were like, yes, that will be very important, but it may also be of interest what type of anisocortic you are tapering. So we looked at, okay, doesn't matter how fast people are tapering. So we compute, we, we have their medication trajectories. And so we could say, okay, they are starting tapering here and they're ending it here. What is sort of the average speed they had over this trajectory? And we calculated the tapering speed in milligrams a day, lenspin equivalent. And what we saw is that it is not the speed by which patients taper anisocortic as well.
33:56 Speaker 01 And I have to note, none of them stopped abruptly, they all did gradual tapering. So this is the difference between gradual tapering and even slower tapering. That's the difference. And then there was no difference, as long as you taper gradually. Tapering even slower does not further reduce the relapse risk. But what is really important is the type of drug that you are tapering. So we saw that patients who used these high affinity antagonists or with the high blocking, dopamine blocking receptor anisocortic, they had the highest risk of relapse. But they also had a faster risk of relapse.
34:35 Speaker 01 So meaning when they stopped the drug, they relapse faster than patients on the low affinity receptors and harsh antagonists. And this categorization links to the idea of what we called dopamine sensitivity, which is the idea that if you block dopamine receptors for a prolonged period of time, the brain will respond to this blocking by upregulating dopamine receptors. And by regulating, we mean that there will, the brain will make more dopamine receptors that are active and that can respond to dopamine. And so that would mean that, okay, if you block dopamine receptor stronger,
35:19 Speaker 01 there may be stronger upregulation. So we have other size stronger upregulation with the high affinity antagonist and the least dopamine upregulation with partial agonist because, hey, with partial agonist, that steals some dopamine signaling. So maybe less need for the brain to have more active dopamine receptors. And I think that because we saw that these high antagonists, high affinity antagonists lap to more relapses and faster relapses, that was an indication for this dopamine supersensitivity, which we then also assessed in our PET study.
35:56 David Puder? Yeah, I was gonna, I was gonna bring this up. By the way, this is, this is incredible. This is, I mean, there may be a lot of mental health professionals who are hearing this for the first time. And if this is at all confusing, guys, please go on to my website psychiatrypodcast.com. I'll have all the links to all these articles. And we'll have a transcript up as well if something's confusing here because I think this is, you know, the first time you're hit with this information, it could be a little bit confusing. Yeah, so I was looking at this, this PET scan. And if you're watching on YouTube, you'll see the PDF and the, the PET scan showing these, these different brightnesses based off of the controls, the partial agonist versus the antagonist.
36:40 David Puder? So walk me through what this PET scan study found here.
36:47 Speaker 01 And so what we did is we wanted to know, okay, is that is dopamine supersensitivity? Do we see more dopamine receptors after, when people have used antipsychotics? But the problem is you do not, you cannot measure this when people are on antipsychotics because, well, there's antipsychotics binding on the dopamine receptor, so you can't measure them. So what we did is we had people taper off antipsychotics and as soon as they really completely stopped. One week afterwards, they were scanned in a PET scan, which stands for positron emission tomography. Meaning they get a radioactive tracer injected, and this radioactive tracer called regular pride. Bind to dopamine D two, D three receptors.
37:32 Speaker 01 Basically, you could see like a Christmas tree with Christmas lights. And whenever there's a blob, you see a light in the Christmas tree, it means ah, there's a receptor. So what we did is we had them scanned one week after they stopped the medication and two months later. And then we differed, of course, between the antagonizing drugs, so is it blocking the receptor? And the partial agonist, so it's a partially stimulating receptor. And we had a group of healthy controls that were comparable in age and sex and so on. And what we saw is that when people had stopped the antagonists, blocking receptors.
38:12 Speaker 01 Those had more dopamine receptors available shortly after they stopped the medication compared to the healthy controls. Meaning that indeed, well, maybe these anticoagulants, they upregulate the dopamine receptors. But what's very interestingly is that the partial agonists, so when patients had used drugs that still stimulated the dopamine receptors somewhat. They did not show this upregulation shortly after, after they stopped it.
38:42 David Puder? That is very interesting, yeah.
38:44 Speaker 01 We do not know, we do not know how and why. But what is crucial, I think, to mention here is that the antagonist group, eighty percent of them had a relapse after they stopped. While in the partial agonist group, it was only one person. Again, it's difficult to make any causal inferences, of course, in here, but it gives us a hint like, okay, maybe this. Dopamine dysregulation associated with antagonists is indeed related to relapse and. That we do not see this upregulation shortly after people stopped.
39:21 Speaker 01 Yeah, maybe it's beneficial. We do not know. I think this should be really for the investigator with future studies, but it gives us a hint.
39:29 David Puder? Yeah, it gives us a hint and it makes sense to me. Like, imagine the dopamine receptor like a door and you are blocking the door with these very strong medication. And so your brain is like, okay, these doors are being blocked. I'm going to need to make more doors. And so that's what the strong antagonists like Haldor or risperdal do.
39:54 David Puder? That being said, in clinical practice, sometimes you need those medications initially, you know, or it's, they can be beneficial to get a quick response or to help people or, you know. So, so I'm not, we're not going all bad on these things, but just to know as clinicians that sometimes this can then upregulate the amount of doors there are, right? And so that's what you're seeing in this PET scan very, very well is there's more doors after you stop the medication. There's more dopamine receptors. And, and that could cause a potential rebound issue.
40:30 Speaker 01 Yeah, and I'm very, I will be very curious to know. So these were all first episode psychosis patients. I think this is also perhaps exclusive to first episode psychosis patients. So I'm not sure whether it will make sense. So for instance, what we don't know is, okay, what if you need an antagonist? Well, you might start with alendipine instead of risperdal and haloperidol. But what would be the effect of adding arapiprazole? I mean, would that mitigate the effect? I think we have no idea whether that might be an option.
41:07 David Puder? I tend to, I tend to not try to like combine those because I know Abilify binds actually tighter. Arapiprazole binds tighter than Haldor or risperdal. So it kind of, it's just, you know, using two antipsychotics for me is, is, is not ideal. I would rather personally optimize one, get the blood level the highest possible. See if it works. If it doesn't work, move to, move to another medication. Okay. One of the interesting findings from this though, was that long-term, what happens to the PET scans?
41:42 Speaker 01 And so long term, we saw that the antagonist group, while they still had an elevation, but it was not significant anymore from the different from the health controls. But we do need to note here that quite a lot of the patients from the antagonist group, they dropped out because they had a relapse within two months. So our group sort of uh was cut into two. I think we might have a power issue there with finding a significant results because so many had a relapse. But then in the partial agonist group, well, except for when they all made it to the second scan. And what we saw is that there's an increase in dopamine receptor availability.
42:25 Speaker 01 So we have potentially more dopamine receptors. And we do not exactly know why and how because what what could it be? Could it be um could it be an opercation? Could that be a regulation in temporal or not? We do not know.
42:45 David Puder? Hmm.
42:45 Speaker 01 I think that's something extremely interesting we should be looking into.
42:50 David Puder? I I think that the the group that did not relapse, the the brain over time normalizes somewhat, right? It it it was like, okay, we needed more doors when there was this blockade. Now we don't need as much doors. And I think this is a general thought that I've had when treating patients is that your brain slowly goes back to normal. When when I'm tapering someone off of, whether it's an SSRI or whatever medication, it may take time for the brain to adjust. And so a slow taper makes more sense so you don't get a rebound issue. I don't know, is that maybe it's too early to say that definitively. But I I like I like that you guys are studying this.
43:35 Speaker 01 And I think I I like the gradual tapering, both because it makes sense from a neurological point of view, but also because it gives you time to intervene in case symptoms emerge. And I think for many patients, finding the lowest effective dose can be eventually the end goal. So for some, yeah, they may want to start out with, okay, let's see if we can go to dose zero. They may end up finding that that is not feasible, not possible, and that finding the low possible dose is the best option. And in that case, doing it really long, long, long, very gradually is crucial.
44:18 Speaker 01 Because only after a few weeks, your brain will have been able to adapt to this new dose. And you know whether or not there will be symptoms.
44:27 David Puder? Um. Well, when you talk in the study, the prior study, the Hamlet study, gradual versus ultra gradual dose reductions, what was the time difference between those things? Like, give me an example with the lanzapine, ten milligrams, like, let's say they're starting with ten.
44:44 Speaker 01 Well, the average was four months.
44:47 David Puder? With the, that was the normal tapering, four months?
44:51 Speaker 01 Yeah, that was, that was about the average. And then they started off from a dose, I think about ten to eleven milligrams a day. And then it tapered off in a course of three to four months. And I think we compared it to even when, whether a person was tapering slower than this or faster than within two, three months. But they never tapered off within two weeks. That was our cut. We did, we excluded all patients who tapered faster than that.
45:23 David Puder? Um hum.
45:25 David Puder? And then the ultra rapid or ultra slow tapering, how long was that?
45:29 Speaker 01 So that was longer than the, the three to four months. And I think we have arranged up until a year. I think that it's quite extreme, but I think in that group, it would be more around six months.
45:42 David Puder? Um hum. Okay.
45:45 David Puder? So, yeah, four months, that, that's about like two point five milligrams per, per month. And was it just a steady decrease? Or did some people drop it faster at first and slower in the end? Any, was it?
45:58 Speaker 01 And we also provided some tapering schedules from the Hamlet study, which can also be found online. And there is a bit of a hyperbolic tapering. So there's initially, there are some larger steps. And then in the end, the steps are somewhat smaller. And the idea behind this is that it matters how much of the. How many of the dopamine receptors are pulled off from antipsychotics? And with with many antipsychotics, you read a therapeutic window fairly easily. So say you read the well, the idea behind a therapeutic window is that you should occupy about sixty to eighty percent of the dopamine receptors. And then that's the sort of the sweet spot. It's therapeutically effective.
46:41 Speaker 01 You have enough dose to be effective, but it's not too of too many receptors occupied. With high doses, if you move, for instance, from ten to five milligrams of lenzepine, that has that makes difference in how many receptors you occupy, but not so much as in the final steps, because then it goes really fast. So we well, we would recommend slightly earlier, slightly lighter steps. And then in the end, be extremely careful. We think the end is very important part, why should why should be extremely careful.
47:17 David Puder? Um. You talked about how it's different between men and women. Can you talk more about that? And specifically, like any recommendations for women that you've been finding? I know also you've looked at um women in different like life trajectories, like menopause and stuff like that. Tell me about that research that you found.
47:41 Speaker 01 Yeah, so for women, we found that it matters not only whether there's a woman or a man, I mean, that differs quite a lot in how many, how much of an antipsychotic they should get, but it's also it's important what hormonal life phase they are experiencing. So, I mean, regarding type of antipsychotics, be careful with risperidone. I mean, it causes hypoleptemia and it may cause breast cancer. So that's a big warning. And if risperidone paired with arpeprazole, because arpeprazole is able to decrease hypercholeptinemia. So that much regarding the type of antipsychotic. So something else we've been doing is, okay, do women on average?
48:26 Speaker 01 So so the problem with antipsychotic prescribing guidelines, at least in the Netherlands, is that they do not differentiate between men and women. So men, women, doesn't matter, they are they are prescribed similar doses.
48:40 Speaker 01 Given that women are inevitably smaller, they have smaller body, they have smaller organs, they have faster blood flow. So if you get give a drug, the blood circulates faster, so medication can reach the brain faster. Intuitively, the it would make sense to have different prescription guidelines, still they are known, which maybe suboptimal. So what we did is that we looked at, okay, we have the University Medical Center, we have many people who draw blood. Let's see if female patients differ from male patients in how much antipsychotic they have present in their blood.
49:17 Speaker 01 And let's see how old they were, because when people enter menopause, we know that estrogen drops. And estrogen is important for how fast a drug is processed by the body. So estrogen is important, especially for olanzapine and clozapine. Because those drugs, when you have high estrogens, those are metabolized slower. So there will be more of the drug presence, I hypothetically. But then if you enter menopause, the menopausal transition, the estrogen drops, and while the drugs may be processed faster.
49:57 Speaker 01 And what we saw in this study is that there was no difference between men and women. If they had olanzapine, like typan, they had inevitably fairly similar blood levels. But it was a difference for olanzapine and clozapine, where women had higher blood levels compared to men. But only in ages before menopause. That we saw the biggest difference. So when women are in the reproductive years and they have high estrogen levels. They also have higher levels of olanzapine and clozapine compared to men. And there's not really any reason why women should have higher blood levels of antipsychotics compared to men. Because we know they also report high um side effect burden compared to men.
50:42 Speaker 01 What was interesting is that so as soon as women enter menopausal ages, we see that the levels decrease to levels that are comparable to men. And so we were really interested in this, like, okay, yeah, women have show decreasing levels of anesthetics when they enter menopausal ages. Can we have a deeper dig into this? Because not every woman is the same, they will have different trajectories. So we did a follow up analysis in which we with machine learning models made different trajectories of men and women of the concentrations over time. Because the beauty, we we focused on Clozapine because
51:23 Speaker 01 Clozapine is monitored, at least in the Netherlands, quite regularly, so we know we have yearly measurements of blood per person for patients. And we know women undergo the menopause transition roughly between the ages of forty to fifty five. So we had a look and we classified the trajectories and what we show is that most women, they show a decrease of Clozapine levels between the ages of forty to sixty. And I think this is, while men mostly remain stable, and that is extremely important because we know that Clozapine is prescribed to treatment resistant schizophrenia.
52:05 Speaker 01 So this is actually a very vulnerable group of women who show reduced levels of Clozapine over time. And I think we should be very, very wary of this because these are women who are in clinical practices, I mean, they are monitored, they are seeing a therapist. And they show reduced levels. They may be incredibly vulnerable for having a relapse. Mm hmm. Especially compared to men. And this showed us that when women enter the menopausal ages, we should really be on the lookout for their levels and their symptoms. We should be monitoring them very closely.
52:48 David Puder? Yeah, I just want to pull up figure two here to show people that can see this online. And you can see with men, it's very stable, the estimated mean Clozapine concentration. Whereas with women, it really does decrease. And we're talking about from around like a little bit above 500 to below 450. And we know that 450 may be that like place where they get that dose response, 350 to 450, somewhere in there. So one, I think practical consideration from reading this paper and thinking about this would be to if you do have a patient that's stable on Clozapine, who's female, who's around 40, 45, you want to get their blood level. You probably will have their blood level, but you want to get it if you don't.
53:33 David Puder? And then you want to adjust the dose as they get older to keep that blood level where that sweet spot is where they are stable.
53:45 Speaker 01 Exactly.
53:45 David Puder? Yeah. And if you have a patient that is not doing as well, this may be the reason why as they get, if they go through menopause, if their estrogen drops and then they're not doing as well on the Clozapine dose that they've been doing well for years. It's counterintuitive to think that the Clozapine level would drop as people get older because usually medication levels increase as people get older. So this is a good clinical pearl here.
54:15 Speaker 01 Yeah.
54:15 David Puder? Wonderful. Wonderful. Yeah. And then tell me about the, your PhD thesis, like what, what are some of the things? If there's anything that we haven't talked about, would there, is there anything extra you want to kind of mention?
54:30 Speaker 01 I think the main message is that ideally we try to personalize the treatment very much to the patient. And then I think that means. That this is an interpersonal process, like giving pharmacotherapy is an interpersonal and social process, that is something we should be acknowledging, I think, very explicitly. And we should try to understand why some psychiatrists are perhaps more effective than others, and are they doing something that we can teach to other psychiatrists? At the same time, we should be very aware of what kind of a drug is a patient using and how the drug influences dopamine. And we should treat women absolutely differently from men.
55:15 Speaker 01 And when we treat women differently, we should be very mindful of the hormonal life phase. I think those are the main takeaway messages of my thesis.
55:24 David Puder? Great. It's been wonderful having you on. It's been great to kind of look through some of these studies. I hope that people listening go back and read them and get curious about them. If there's something you didn't understand or something you want to look at, we'll have a transcript on my website psychiatrypodcast.com, which I have a team that goes through it to make sure the wording is correct and we try to smooth things out where possible so it's more readable and we'll have all the citations there. But yeah, any final thoughts, any final things that are still on your mind that you want to mention?
56:00 Speaker 01 I think we've covered a lot already and I'm very curious to see what the implications of these are.
56:08 David Puder? Yeah, I think this is great. Have you read the study on reflective function and therapist effect? Have you looked at that one yet? Okay, I'm gonna have to like, I'm gonna have to show you this slide here. So there was a study, so I've been curious about therapist effect for a while, okay? And initially, the best study that I found on therapist effect was this study where they videotaped therapists and they had the therapists, let's see, this is it, they videotaped therapists responding to difficult interpersonal questions from actors, like, so they had
56:53 David Puder? clips, and then they rated the therapist's response to these difficult interpersonal situations that come up. Things like when a patient may say something like, "You can't help me," or... I don't know what to talk about, or only therapist's, only the therapist's opinion matters. You know, like different conflicting things that the, that the patient can say. So they videotaped the therapist and they looked at the, the scoring and they looked at how that scoring related to the therapist's outcomes on the OQ 45 on a bunch of the patients they were treating. And they found like a correlation of point four seven.
57:35 David Puder? It's like somewhat, you know, pretty good, pretty good, like a pretty good predictor, one of the best that I've found, you know? But then I stumbled upon this study called therapist reflective function, therapist attachment style and therapist effectiveness by Coligan, John Coligan. I'm still trying to get him on my podcast. So if anyone knows John Coligan, let me know, tell him, tell him to respond to my emails. So here we had 25 therapists who were seeing 1,001 patients and they did it OQ 45. But on this, they did the adult attachment interview and they scored it with reflective function. Okay.
58:14 David Puder? And so reflective function is like a very, it's, it's kind of like the ability to mentalize your own emotions, your parents' emotions, what was going on, the why of your childhood. And so then they looked at the adult attachment interview, the reflective function score, which goes from negative one to nine, nine being the highest. And they found, and they broke them, they broke the therapists into three groups. Low reflective function score therapists had no change in the OQ 45 at all. So patients came in with an OQ 45 of 80, they left with an 80 at session 10.
58:53 David Puder? It's like, uh, the patients who had medium reflective function had scores that dropped from around 80 to, let's see, this is around 73. Okay. And the patients with high reflective, or the, the therapists with high reflective function scores had a draw from 80 to.
59:18 David Puder? Sixty seven. So they looked at the variance of the therapist effectiveness, and they found a seventy point five percent variance was accounted for by reflective function, which when I saw that, I was like, like, this is huge. That's a huge number, right? Seventy point five percent. So that took me on a journey to investigate their reflective function. I've done a bunch of episodes on this. I won't belabor it. I'm actually releasing an episode before, our episode with Miriam Steele, who's an author, one of the original authors of reflective function. And I lead cohorts that try to
1:00:02 David Puder? increase, provide a reflective function. And so in the future, we may be doing research on that as well. But it's something to think about as you, it's kind of like, okay, there's therapeutic alliance, there's the ability to connect with patients, but I think there's also therapist reflectiveness, which is based on the adult attachment interview.
1:00:26 Speaker 01 So what do you think is important about the reflective ability of psychiatrists that is so influential?
1:00:34 David Puder? So when a difficult interpersonal situation occurs with a patient, it stirs up our own stuff, right? And I think that people with high reflective function have done the work to understand their own countertransference, their own reaction to patients, to be able to put words to it in their own mind, and then to be able to not necessarily get emotionally evoked in a way that would negatively impact the connectedness between you and the client. I think someone with high, the high ability to reflect on early attachment stuff.
1:01:20 David Puder? It hits, it hits the provider in an area that they can't fake. So the adult attachment interview, it's impossible to study for it like you would a normal test. If you go in there and you try to have high reflectiveness, you, you will be found out, right? Like, there's no way of hiding because you've either done years of your own personal therapy that would allow you to have higher reflectiveness, or you haven't, essentially.
1:01:58 Speaker 01 And so do you think this is something that's innate, that some people just do better than others? Or do you think this is something we can train with therapists? Because I think one part of the beauty of treatments and therapist effect is that there are parts that we can still modify. These are the very, I think, positive parts of patient's recovery, where we can still find places for optimization.
1:02:25 David Puder? I'm glad you asked. So, let's say you had a, a provider who had borderline personality disorder. In general, someone with borderline personality disorder has lower reflective function. So they start out in this one study on transference focused therapy versus dialectical behavioral therapy versus supportive psychotherapy. They start out at around 2.8 people with borderline personality disorder. So this is a scale, remember, from negative one to nine. So 2.8 is, is a low score. So by the end of the study, by one year of twice a week psychotherapy, they're able
1:03:07 David Puder? to go up to about a 4.1 with the transference focused psychotherapy. So, think about like a provider who is in years of therapy, years of good therapy. They, they will continually, hopefully, increase their reflective function score. And if they're utilizing good supervision.
1:03:28 David Puder? And if they're approaching life with this kind of roadmap on how to increase their reflectiveness, then yeah, I think absolutely, I think anyone can increase their reflectiveness. I think there are some people who probably start out higher than other people, obviously. I think that it doesn't seem to be related to IQ. People who go to prison have lower reflective function scores. People with alexithymia have lower reflective function scores. People with eating disorders have lower reflective function scores. And people with BPD have lower reflective function scores. So there are pathways of treatment for all of these types of groups of people that I just spoke about.
1:04:10 David Puder? And so getting effective treatment can, over time, increase your reflective function. So yeah, I think it's hopeful. I think it's not as easy as like you're going to go to a weekend seminar. You're going to learn some empathy skills. Because empathy breaks down, especially in close attachment relationships, right? Like you could have a provider, for example, who's very empathic towards their patients, but maybe struggles with their significant other. Why are they struggling with their significant other? Because of their early attachment relationships. Maybe because of that gap in reflective function with their early attachment relationships
1:04:51 David Puder? would cause them to struggle with later relationships as well in a similar way. And so maybe they know how to empathize with people they're a little, they have some distance with, right? But when they get into a close interpersonal exchange with a patient, maybe a more sick patient, maybe that's when the countertransference comes up. That's when the attachment machinery comes up that's unprocessed. So that's why there seems to be, actually, if you look at the research on therapist effect, it seems like there's a higher therapist effect with more sick patients than with mildly ill patients.
1:05:34 David Puder? Like as the illness goes up, right?
1:05:37 Speaker 01 Yeah, exactly, yeah. And I think the same holds true for paranoia. As paranoia goes up, so more severe cases, the therapist effect goes up.
1:05:48 David Puder? Yeah, because it's, it can be very, uh, it can be very jarring. It can be very confusing on what to do. Therapists are not often trained on how to deal with psychotic patients. I have a therapist that works for me now, who, when I, when he first started working for me, he was like, "The patients that you're sending me are very ill compared to every patient I've seen in the past." And it's because the patients that come to a psychiatrist, especially maybe like the ones that maybe I attract, especially ill ones because of the podcast and because people are, who find me are really seeking for something, you know, that maybe they haven't gotten. So he says, "The patients that you're sending me are really ill."
1:06:33 David Puder? And I've had to help him work with learning how to be patient with the psychotic symptoms and how do you deal with them? So there is, there is a degree of specialized training and getting used to treating that population. I think that is very vital that providers need to go through. Let me ask you, how did you get interested in this though? Because it seems like, like are you, it seems like you're more on the research side, but there's a fascination with this, right? You're not treating, are you treating patients? Are you providing therapy for these clients? Are you mostly researching?
1:07:08 Speaker 01 I'm a hundred percent research, yeah. I'm a neuroscientist by training. But I feel very interested in how people perceive and experience the world. And I can be studying the brain, of course. I am studying the brain, but I am studying the brain to understand how and why people experience certain, experience certain environments and ways, the way they do. And now I'm very interested also in improving treatments and lives of patients with psychosis. And I think it is.
1:07:44 Speaker 01 I think psychotherapy is such a personal and social experiences and I feel that if psychiatrists are just left out of the picture, while they are such a massive part of how a person will respond to the treatment, we are missing something completely.
1:08:01 David Puder? Um hum.
1:08:01 Speaker 01 I I wanted to at least draw attention to this because I think it's an overlooked or overlooked issue, surely. I think we should be more aware of how they are as a person important into patient's treatment and how they as a person can also make a positive benefit. And for instance, the trainings you mentioned that there is also a room for improvement. So if you have this positive ability, maybe you have the complete positive potential you can reach, sure, or you can also strive to become even a better psych- uh psychiatrist.
1:08:41 Speaker 01 And that does not only entail knowing what type of drugs and what type of dosages to prescribe, that also entails knowing how you should respond, how you should deal with patients. And that that interpersonal part is something that's so crucial and that may very well need lifelong learning rather than studying guidelines in the evening.
1:09:04 David Puder? Um, uh, have you heard of Michael Garrett? He came on my podcast, uh, great, great book on psychotherapy for psychosis, integrating CBT and psychodynamic. Have you heard of him? He's a great, he's a great resource. If if anyone's listening to this and wants to go back to that episode to to hear some of his, some of his insights were really profound and um, yeah, I'd like to do more. I think there is a certain level of just knowing about psychosis, knowing about, um, for example, I'm I'm doing an episode, it may air before years on delusions and I have two hours with Dr. Cummings, who's like, uh, he works at a state hospital, so it's the most severe of severe patients, like the patients who are murdered someone or had some
1:09:50 David Puder? some crime that with a psychotic episode involved and led to being hospitalized extensively for for years, right? So to look at the most ill of ill patients can sometimes give us some more. Patience, some more understanding, some more calm, right? When we're treating patients. Because, you know, one of the things that we try to help families do with patients with schizophrenia is to be calm and to be very like, to find their own peacefulness. And if they're yelling, if they're agitated, their, their son or daughter with schizophrenia is not going to do us well, right? And so this is one of the things I think we could do as providers is to, to find our
1:10:31 David Puder? own ability to become very calm in the midst of someone else's psychotic ramblings, psychotic thoughts. So, well, great. Shall we say goodbye for today? And it was very nice to meet you.
1:10:48 Speaker 01 It was great talking to you.
1:10:50 David Puder? Yeah, so I'm, I'm like, you're already churning out tons of great articles. I expect to have you back at some point as you publish more papers and you can continue to teach us and we can find an integration between the, the research and the brain science and how it can help us understand and help patients. So, thank you for coming on.
1:11:11 Speaker 01 Thank you for having me.
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