Psychiatry & Psychotherapy Podcast - Psychiatrist Effect in First-Episode Psychosis: HAMLETT Study, Antipsychotic Tapering, Dopamine Supersensitivity & Sex Differences with Franciska de Beer

Episode Date: April 3, 2026

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.   By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog Link to YouTube video

All right, welcome back to the podcast. Today I'm thrilled to be speaking with Francesca DeBier. She is a talented researcher, soon to finish her PhD at the Center for Clinical Neuroscience and Cognition at the University Medical Center, Cronican 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 Psychiatrist Effect on Positive Symptoms, 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's 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 interest 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. And so hopefully we'll have some of the new. new research on that discussed in this episode. So welcome to the podcast. Thank you for having me. So maybe we could start with paper on Psychiatrist Effect and go from there. So do you want to

describe the basic findings of this research? Yeah, sure. I love your introduction and I think the McKay article, you love, I love it so much as well. So I think I love it so much as well. think one of the main issues when we talk about psychiatry is that after all we want to improve patients' recovery, right? And the main way we go about it is look at, 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. 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, recover from esophosis in that treatment outcomes. Beautiful. Yeah.

So what we did is we have a nationwide study, the Hamlet study, that has about 350 patients where we use slightly less of them from many different psychiatrists. And that allowed us to have 18 psychiatrists with an average 11 patients but psychiatrist. And so we could see, okay, does the patient? outcome of an overt period of 12 months, so over one year, depends on the psychiatrist. And we indeed thought that that was the case. So we found that the psychiatrist could explain about 10% of the patient's outcome after one year, which is quite a decent amount. And what was quite interesting is that it's not only about the psychiatrist 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 psychiatrist, but also the way psychiatrists prescribed medication that matter. 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? Exactly, exactly, yeah. So during this study period of 12 months, they were initially randomized to either reduced 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-year-in and 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, well, increasing always, but reducing the dose or not to. 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 are on YouTube, you can see this. So we'll try to describe it for those listening. So describe for the audience what, what we're seeing here in terms of psychosis severity change scores based on different psychiatrists? Yeah, so what we see here is a bar plot where we see one bar per psychiatrist. And what's plotted on the my axis is, does a patient improve or worsen in their amount of psychotic symptoms? So what we did is we measured symptoms of ferriti with the pons, the positive

and negative syndrome skill, 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 skill. We did this shortly after they were in remission, so three to six months, and we did it again after one year. And basically what we do is how does one improve or worse than over the period of a year. And we averaged those improvements and decreases over all patients of a certain psychiatrist. So a psychiatrist had an average 11 patients, so you have an average of 11 patients. What we see here is that some psychiatrists show a marked, well, a slight worsening, but not too different from zero. So basically the patients remain quite stable. Then there are also some of us

indicating that some psychiatrists, they actually show quite a marked improvement of the course of a year. 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. This may be a bit controversial to say, but there's the belief that well, there are some clinicians that may be more effective than others. Some literature suggests it's maybe 15 to 20 percent of psychiatrists, well, having better outcomes and 15 to 20 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 bark plot, I think, quite effectively shows that. The variance explained by psychiatrists was 9.1%. And the variance explained after controlling for antipsychotic dose was 9%, which was interesting to me. 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. Exactly. And I think the personal skills of psychiatrists, the communication skills are of massive importance. And I can imagine, especially with psychosis patients where 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 patients and massive communication skills to build this level of trust. So a patient,

is 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, the psychiatrist's act is of major importance. Yeah. One of the things I've tried to convey to residents over the years is the amount of energy that we a psychiatrist 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 variants in this group. Tell me about that amount. It seems, you know, it's about three, four times as much, right?

as the effect of the psychiatrist. So baseline severity was very potent in predicting how well someone was gonna do. Tell me about that and what you think about that number. Yeah, so it basically means that how well you recovered initially, predict 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're recovering. about it very poorly because then your prognosis is somewhat bleaker. Yeah, and I think that that is, it's a bigger impact than psychiatrists 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 9%, which is interesting to me. Some things didn't have an effect at all, right?

like the frequency of the psychiatrist contact, medication non-adherence, effective treatment center, how do you make sense of these things? Yeah, so I think the frequency of psychiatrist was overall fairly similar, so I'm not sure 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 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 of variety.

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? And also, who benefits from what? Because there may be a young male early 20s, they may need different treatment needs than someone, for instance, women being vulnerable to these psychotic episodes

during period of menopause where there are also other semantic complaints. So, yeah, I'd love to be looking at what the best combination would be per person. 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. As next to how many symptoms, patients experienced in their daily lives, we also looked at how well they were able to get along with the daily functioning. You can think of how well they were able to communicate with other people doing the household course, whether they will be able to work or not. They rated their own daily functioning, and we saw that also similar to the psychosis severity data. Patients with some psychiatrists showed better improvements, and better improvements in this case means a greater reduction in symptoms of severity in daily. functioning.

And this, yeah, this was 10%, which was quite, quite a lot. 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 their anti-psychotic drugs. And I think here that is this combination of this interpersonal aspect, like how much trust is someone being able to build up with a patient so how much openness is that about undergoing symptoms and how well is the 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. And I think some psychiatrists may do these adjustments more efficiently than others. Yeah, so, you know, you. 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? I think that's a very intriguing, difficult question to 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. And I think the process of shared decision making is crucial.

And for instance, 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 whenever possible, of course, I understand there may be cases that's not possible. Whenever possible, this should be an open conversation. Yeah, I think it's a lot of the issues that I run in my own private practice are things like anisinomia, like where the patient has no insight into their illness. This can create increased difficulty in even getting the patient to agree to take a medication. Sometimes I've started kind of a new

approach with just doing pure psychotherapy without medication for the first couple 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. 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? I think the honest insight is a very, very good one because where do we start if someone is not willing? And I think this is an extremely difficult one. But important one to address before starting well, LIAs or perhaps more admitting someone to a hospital. So I like your approach very much on first trying psychotherapy in the first case.

How is it in the Netherlands? What is the approach for first episode psychosis? Like what normally happens to a patient? Are they admitted to the psychiatric hospital? or they started on medications in the psychiatric hospital, or they started outpatient. That differs greatly on whether or not hospitalization is necessary. So in many cases, there is a hospitalization,

and in those cases, there are often, endosocotics prescribed, say 10 milligrams. So lenzapine 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 roots. And it depends on whether someone was, whether the psychosis derailed a lot.

So hospitalization was necessary or the person and the environment interfered in time to go to a fecalate GP and start aniseachotic, either there or with a specialized psychiatrist. I've heard about in Amsterdam the rates of high use of high potent THC. Is this play a factor in how you determine if you're going to try to take someone off of an antipsychotic or not? Has there been any thought on that? Well, I think that implicit. That was the assumption that when someone has a drug-induced diagnosis and the person has really stopped, using the antipsychotics, they may be the well better suited persons to taper off endicotics.

And interestingly, very, very recently, I have done a study on what happens after people stop endosacotics. So patients tapered out of their drugs, not all of them, but part of them in the Hamlet study. And when it tapered, some of them actually reached those errors, so they completely discontinued. And in those patients, I looked okay, but if they discontinued, what happens? after that stopping point. And we followed them up for about four years. 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 end of the academics barely quickly again, so say after five months. One group of these was also hospitalized very easily or quickly. So about after four, five months, a subset of patients 9%. I still think 9%

is not too many, but 9% of the patients who stopped, they needed a hospitalisation and typically these were male patients with lower education in quite high care needs, so about double the care needs of other compared to others. There was also a group of patients

who was able to stop medication for a very long time, did not relapse, did not have hospitalisation, and those were people who were people who were fairly young, the first psychosis. They had good education, quite high functioning, the highest occupational rates 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 a part of these patients who were able to stop medication very well with those who had initial drug use, but then most likely stop drugs or at least way, way less than initially. And those may be the patients that could do better without medication. Okay. That's great.

That's good to hear. Let's talk about the JAMA article. This is, I'm just going to pull this up so people can see what this looks like. it says early dose reduction or discontinue versus 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 a 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 So for people's background, what we did is we randomized about 350 people who experienced a circotic episode for the very first time, so the first episode of Cocytics.

And they were randomized to either dose reduced young acucydics, faster than guidelines prescribed. So within the first year after remission, or they could have to maintain the dose in which they reached 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 three labs, but I mean, it may have long-term functional benefits. And in fact, there was a doctor study that showed that in a long-term, after seven years, the group who those reduced early had long-term functional benefits.

And that caused, at least in the Netherlands, quite some of hippie with some psychiatrist, those 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 control trial to give some more solid, at least in a bigger group, evidence. So what we saw after, we looked, okay, so what that happens after one year after people were in remission? And we saw that those who dose reduced early had a higher risk of relapse compared to those who maintain stable on the 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 meal patients.

the quality of life reduced in the dose reduction group in the male patients, not in a female patients. I think that is fairly interesting. And it caused the question of, okay, but were the female patients dose too high initially then? Or are they better able to dose reduce? I mean, does it have something to do with potentially larger social groups or 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

mention here. Now, we also, this was short term. Now we were interested, of course, in what 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 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 barely similar doses. Actually, the dose reduction group even had a slightly higher dose than the maintenance group. So what we see here is that there's functional benefit of early dose reduction, 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's effect here. So does it, we think that the process of early dose reduction will have benefits. But then what is it 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 those you choose.

They do this together, extremely, extremely slowly. So those reduction is a process of months. 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 decisions. Also, they experience what happens to them when they lower the dose. I mean, they experience perhaps that one lower doses, they have more symptoms, and I 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, so there have been two previous studies that have contradicting results. One said, okay, a long-term early dose reduction is beneficial, and that one was open label, so both patients and psychiatrists knew what was happening. There's also one that was double-blanky. it. 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 there 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. You know, I'm also thinking about how if you're a psychiatrist and outpatient, yet. And this is kind of what you were saying, but maybe I'll just reiterate it one more time. It's like 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 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, if, if, if, if, if, if, if, if, If all of the medication is taken away, then their insight can be completely gone. 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 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, we're 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 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 yeah yeah and I think

there's a crucial aspect here is that it does really matter that there's good monitoring so when you do to do is 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 the Netherlands, it's also done by nurses and psychologists. So the workload is slightly, well, distributed among people. And I think this is crucial, because if you don't have what caregivers who know what,

I mean, everyone has these relapse symptoms, which are quite personal, like distress, the sleep, is it a hearing voice 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 dosges without any guidance. I think that's the worst idea ever.

So we need to be able to provide the very good monitoring. Yeah. Yeah. Very good. Okay. And then there was a letter that you guys did that was. 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 talking about, but what came from this letter, what I was thinking about it was 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. And this, you know, like if they're on a strong dopamine blocker, like halidol, risperidone versus weak D2 antagonists like olanzapine, quatyapine, or a partial

d2 agonist like eripipipazol. 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. And 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 anisicardic, it doesn't really matter what type of anisicardic it is, but you're more into, okay, how much dose reduction is it? And then the dose reduction, yeah, would be sort of similar among all online saccharics. But when you think about it, unlike psychotics work differently on the dopamine system. There are quite some differences.

there are these antagonists, right? They bind to dopamine D2 receptors, and they actively antagonize, so they inhibit the dopamine signaling on that receptor. And you have anisococytic's in the antagonists who do this very heavily, so they bind very tightly, and they block a lot.

We call these the high dopamine D2 affinity antagonists, any like heropatol and risperidone. And there are anesthetics, yeah, they also bind, but less tightly, and if they bind, they inhibit. These are olensopine and katapine. We only have one closopine. So we categorize closopinus in this group two, but we only had very, very few cases of closopine use in the hamlet study

because, well, these were limited patients, and typically in the Netherlands, you give closopine to treatment resistance. And then there's a different group of endless codecs that, well, they bind with very high affinity 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, there is antagonism, meaning there's stimulation, partial stimulation. So there's stimulation, but less than endogenous dopamine stimulator receptor,

so meaning that in the end you have a reduction of your dopamine signaling. Because anisicotics, they all will reduce dopamine signaling in one way or another. So that gives us with the three types of anisicotic drug. 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. 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 endicotic you are tapering. So we looked at, okay, doesn't matter.

how fast people are tapering. So we compute, we have their medication trajectories. 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, volensipine equivalence. And what we saw is that it is not the speed by which patients taper and isocardics. Well, 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, so with the high blocking, dopamine blocking receptor, and oesychotics, they had the highest risk of relapse. But they also had a faster risk of relapse, meaning when they stopped a drug, they relapse faster than patients on the low-affinity receptors and the parochial agonists. And this categorization links to the idea

of what we call dopamine super 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 while regulating, we mean that 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, there may be stronger upregulation.

So we have authorized stronger upregulation with the high-affinity antagonist and the least dopamine of regulation with partial organics because, hey, with partial a organism, there's still 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-offenty antagonists, led to more relapses and faster relapses, that was an indication for this dopamine super-sensitivity, which we then also assessed in our pet study. Yeah, I was going to bring this up.

By the way, 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 PET scan showing these different brightnesses based off of the controls, the partial agonist versus the antagonist. So walk me through what this PET scan study found here.

And so what we did is we wanted to know, okay, is that is dopamine super sensitivity? Do we see more dopamine receptors after when people? people have used aniseychotics. But the problem is you do not, you cannot measure this when people are on an anesthetics because, well, there's endosocotics binding on the dopamine receptor, so you can't measure them.

So what we did is we had people to taper of an anesthicotics, 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 intracer injected, And this radioactive tracepracea called Recloprides binds to dopamine D2D3 receptors. Basically, you could see like Christmas tree with Christmas lights.

And whenever there's a blob, you see a light in Christmas tree. It means, ah, there's a receptor. So what we did is we had them scanned one week after they stopped it, the medication, and two months later. And then we differed, of course, between the antagonizing drug. so is it blocking the receptor and the partial agonist, so it's partially stimulating the 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, those had more dopamine receptors available shortly after they stopped the medication compared to the healthy controls,

meaning that indeed, well, maybe these endicococytes, they upregulate the dopamine receptors. But what's very interesting, really, is that they pass your agonists, so when patients had used drugs, they're still stimulated the dopamine receptor somewhat, they did not show this upregulation shortly after they stopped it. That is very interesting, yeah. We do not know how and why. But what is crucial, I think, to mention here is that the antagonist group, 80% 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 cost or 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, yeah, maybe it's beneficial. We do not know. I think this should be really further investigated with future studies, but it gives us a hint. 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, that's what the strong antagonists like Haldol or Rospheredol do. That being said in clinical practice, sometimes you need those medications initially, you know, or they can be beneficial to get a quick response or to help people or, you know, so 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 that could cause a potential rebound issue. Yeah, and I'm very, I will be very curious to know. So these were all first episodes ofosis patients.

I think this is also perhaps exclusive to first episodes of causes patients. So I'm not sure whether it would make sense. So for instance, what we don't know is, okay, what if you need an antagonist? Well, you might start with a Lenzapine instead of risperidone and haloperidol. But what would be the effect of adding aeroproposol? I mean, would that mitigate the effect? I think we have no idea whether that might be an option. I tend to not try to like combine those because I know Abilify binds actually tighter.

aeropipyzo binds tighter than halidol or risperto. So it's just, you know, using two antipsychotics for me 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 another medication. Okay, one of the interesting findings from this, though, was that long term what happens to the PET scans? Yeah, so long term, we saw that the antagonist group, well, 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 was cut into two. I think we may have a power issue there with finding a significant. results because so many had a relapse. But then in the partial organist group, well, except for one, they all made it to the second scan. And what we saw is that there's an increase in dopamine receptor availability. So there are potentially more dopamine receptors. And we do not exactly know why and how, because what could there be? Could it be, could it be an up regulation? Could that be a precarulation being temporal or not? We do not know. I think that's something

extremely interesting we should be looking into. I think that the group that did not relapse, the brain over time normalizes somewhat, right? 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 I'm tapering someone off of whatever 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 like that you guys are still. And I think 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 sometimes emerge. 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 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. 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.

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? Give me an example with the olanzapine 10 milligrams. Like let's say they're starting with 10. Well, the average was four months. That was the normal tapering, four months? That was about the average.

And then they started off from a dose, I think, about 10 to 11 milligrams a day. And then they tapered off in a course of three to four months. And I think we compared it to even whether a person was tapering slower than this or faster than within three months. But they never tapered off within two weeks. That was our cut. We excluded all patients who tapered faster than that. And then the ultra-slow tapering, how long was that? So that was longer than the three to four months.

I think we have a range up until a year. I think that it's quite extreme, but I think in that group it will be more around six months. Okay. So yeah, four months, that's about like 2.5 milligrams per month. And was it just a steady decrease, or did some people drop it faster at first and slower in the end? Any thoughts on that?

We also provided some tapering schedules from the Hamlet study, which can also be found online. And there's a bit of a hyperbolic tapering. So initially there's some larger steps, and then in the end, the steps are somewhat smaller. And the idea behind this is that it matters how many of the dopamine receptors are pulled off from endosacutics. And with many and thoseococytes,

you read a therapeutic window barely easily. So say, you read the idea behind a therapeutic window the ways that you should occupy about 60 to 80% of the dopamine receptors and then that's the sort of the sweet spot. It's therapeutically effective. You have enough dose to be effective, but there's not too many receptors occupied with high doses. If you move, for instance, from 10 to 5 milligrams of lenzapine, that makes difference in how many receptors you occupy, but not so much. It's in the final steps because then it goes really fast. So we would recommend slightly early, a slightly large steps.

And then in the end, be extremely careful. We think the end is a very important part. Why you should be extremely careful? 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 women in different life trajectories, like menopause and stuff like that.

Tell me about that research that you found. Yeah, so for women, we found that men is not only whether there's a woman or men. I mean, that differs quite a lot in how many, how much of an endosacetic they should get, but it's also important what hormonal life phase they are experiencing. So, I mean, regarding type of anaicotococytics, be careful with risperidone. I mean, it causes hyperlactemia and it may cause breast cancer. So that's a big warning. And if resperidone paired with aproposol, because heraproposol is able to decrease hyperprolactinemia.

So that might be regarding the type of anaestocytic. So something else we've been doing is, okay, do women on average? So the problem with, and this codeic 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 prescribed similar doses. Given that women are on average smaller, they have smaller body, they have smaller organs, they have faster blood flow. So if you give a drug, the blood circulates faster so medication can reach the brain faster. intuitively, it would make sense to have different prescription guidelines still they are non, which maybe suboptimal.

So what we did is that we looked at, okay, we have the University Medical Center, Groningen, we have many people who drop blood. Let's see if female patients differ from male patients and how much anesthetic they have present in their blood. Let's see how old they were, because when people enter menopausea, 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 Alenzepine and Plosopine, because those drugs, when you have high estrogens, those are metabolized slower, so there will be more of the drug presence, hypothetically. But then if you enter menopause, the menopausal transition, the estrogen drops, and while the drugs may be processed faster.

And what we saw in this study is that there was no difference between men and women if they had an elenipine and tight pine. They had on average fairly similar blood levels. But it was a difference for alenzepine and closet pine, where women had higher blood levels compared to men, but only in the ages before menopause. that we saw the biggest difference. So when women are in the reproductive years and they have higher estrogen levels, they also have higher levels of lancepine and closopine compared to men, there's not really any reason why women should have higher blood levels

of antipsacadics compared to men because we know they also report high side effect burden compared to men. What was interesting is that so as soon as women enter menopause or ages, we see that the levels decrease to levels that are comparable to men. And so we were really interested in this, like, okay, women show decreasing levels of unicodics when they enter men in a porousal 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 their blood concentrations over time. Because the beauty, we focus on closopine, because closopine 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 on the go, the menopause transition roughly between the ages of 40 to 55. So we had a look and we classified the trajectory. And what we show is that most women, they show a decrease of closopin levels between the ages of 40 to 60. And I think this is, while men mostly remain stable, and that is extremely important because we know that closipine is prescribed to treatment-resistant schizophrenia.

So this is actually a very vulnerable group of women who show reduced levels of closine 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, 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. Yeah, I just want to pull a 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 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 chlozapine, 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. 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. Exactly. 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. Yeah, absolutely. Wonderful. Wonderful. Yeah, and then tell me about your PhD thesis. Like what are some of the things?

If there's anything that we haven't talked about, was there anything extra you want to kind of mention? I think the main messages is that ideally we try to personalize the treatments very much to the patient. And I think that means that. 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. And when we treat women differently, we should be very mindful of the hormonal lifease. I think those are the main takeaway messages of my thesis. 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, 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?

I think we've covered a lot already. And I'm very curious to see what been qualifications of these 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 going to have to like, I'm going to 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. The videotaped therapists responding to difficult interpersonal questions from actors, like, so they had clips, and then they rated the therapist 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, to talk about or only therapists, only the therapist's opinion matters, you know, like different conflicting things that the patient can say. So they videotape the therapist and they looked at the scoring and they looked at how that scoring related to the therapist outcomes on the OQ45 on a bunch of the patients they were treating. And they found like a correlation of 0.47. It's like somewhat, you know, pretty good, pretty good, like a pretty good predictor, one of the best that I found, you know. But then I stumbled upon this study called Therapist Reflective Function, Therapist Attachment Style and Therapist Effectiveness by

Colagon, John Colagon. I'm still trying to get him on my podcast. So if anyone knows John Colagin, let me tell him, tell him to respond to my emails. So here we had 25 therapists who were seeing 1,001 patients, and they did at OQ45, but on this they did the adult attachment interview and they scored it with reflective function. Okay. And so reflective function is like a very, 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 the therapists into three groups.

Low reflective function score therapists had no change in the OQ45 at all. So patients came in with an OQ45 of 80, they left with an 80 at session 10. It's like 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 therapist with high reflective function scores had a drop from 80 to 67. So they looked at the variance of the therapist's effectiveness, and they found a 70.5% 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 70.5%. So that took me out a journey to investigate their reflective function. I've done a bunch of episodes on this.

I won't belabor it. I'm actually released 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 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. So what do you think is important about the reflective ability

of a psychiatrist that is so influential? 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 ability to reflect on early attachment stuff, 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 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 reflectivity.

or you haven't, essentially. 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's effect is that there are parts that we can still modify. These are the very, I think, positive parts of patients' recovery where we can still find places for optimization.

I'm glad you asked. So let's say you had 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 transverse focus 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 of remember from negative one to nine. So 2.8 is a low score.

So by the end of the study, by one year of twice a week psychotherapy, they're able to go up to about 4.1 with the transfers focused psychotherapy. So think about like a provider who is in years of therapy, years of good therapy. They will continually hopefully increase. their reflective function score. And if they're utilizing good supervision 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 the lexothymia 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. 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 relationship. 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 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, 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. Like as the illness goes up, right? Yeah, exactly, yeah. And I think the same is how it's true for paranoia. As paranoia goes up, so more severe cases, the therapist effect goes up.

Yeah, because it can be very, 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 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 one that maybe I attract especially ill ones because of the podcast and because people 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. 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 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, are you, it seems like you're more on the research side, but there's a fascination with this, right? You're not, are you treating patients? Are you providing therapy for these clients? Are you mostly researching?

I'm 100% research, yeah. Neuroscientist's training. But I feel very interested in how people perceive and experience the world. 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 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, I think psychotherapy is such a personal and social experiences and I feel that if psychiatrists are just left out of the picture while there is such a massive part of how a person will respond

to the treatment, we are missing something completely. I wanted to at least draw attention to this because I think it's an overlooked or overlooked issue, surely. I think people should be more aware

of how they are as a person important into patient treatment and how they as a person can also make a positive benefit. And for instance, the trainings you mentioned that there is also room for improvement. So if you have this positive ability, maybe you have the complete positive potential you can reach pure or you can also strive to become even a better psychiatrist. And that does not only until knowing what type of drugs and what type of doses 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. Have you heard of Michael Garrett? He came on my podcast. Great book on psychotherapy for psychosis, integrating CBT and Psychodynamic. Have you heard of him? He's a great resource. If anyone's listening to this and wants to go back to that episode to hear some of his insights were really profound. And yeah, I'd like to do more.

I think there is a certain level of just knowing about psychosis, knowing about, for example, I'm doing an episode, it may air before years on delusions. And two hours with Dr. Cummings, who's like he works at a state hospital. So it's the most severe of severe patients, It's like the patients who murdered someone or had some crime that with a psychotic episode involved and led to being hospitalized extensively for years, right?

So to look at the most ill of ill patients can sometimes give us some more patients, 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 son or daughter with schizophrenia is not going to do as well. Right. And so this is one of the things I think we could do as providers

is to find our own ability to become very calm in the midst of someone else's psychotic, rambling, psychotic thoughts. So, well, great. Shall we say goodbye for today? and it was very nice to meet you. It was great talking to you. Yeah, so 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 research and the brain science and how it can help us understand and help patients. So thank you for coming on. Thank you for having me.