So we're going to get started, it's great to see a full room, thank you, thank you so much for being here. So I'm Mauricio Toen and I'm at the University of New Mexico and I've been working in bipolar disorder my whole professional life. So again, thank you, thank you for being here. And we'll be introducing the other colleagues as they come to the podium. So here are my disclosures. As you can see, I even had experience in the pharmaceutical industry, I was an industry scientist for Lilly, I was in academia, then I worked as an industry scientist and I'm back in academia and I've been, the last nine years I've been in New Mexico. So we're going to be talking about bipolar depression and as you can see in this slide, we're comparing bipolar with major depression. And as you can see, bipolar depression, the prevalences of comorbid conditions is larger in all types of bipolar disorder compared to depression. If you look at substance abuse, the majority of patients with bipolar disorder have a comorbid substance use disorder, which is not the case for major depression, as you can see, just 18%. The same thing with psychiatric comorbidities. When we think about anxiety disorders, we usually think, oh, they're associated with depression, we even have this new DSM-5 term, anxiety depression. But as you can see here, if you look at the prevalence for bipolar, actually bipolar is the one that has the most comorbidities, being psychiatric and being substance use disorder. So 80 plus percent of patients with bipolar disorder suffer from comorbid anxiety disorders. So as you can tell, the challenges of treating bipolar disorder are larger than those treating major depression, for some of the reasons that we've mentioned. And of course, bipolar disorder is the most lethal of all psychiatric conditions. So same as our colleagues in other medical branches, we make decisions of life and death, we certainly do when we see a patient in the psych emergency service, I need to make the decision, do we keep or we send this patient home? So big life and death decisions. Let me now move to... So what is the impact of depression in general in bipolar disorder? So as you can see, blue is well, okay? So we usually think of bipolar I as more severe than bipolar II. Well, it depends what you mean by severity. If it's agitation, need for hospitalization, yes. But if you look at being well, bipolar II patients spend more time ill, 50% of the time of their lives, once they're diagnosed with bipolar II, they experience it being not well, the majority of the time. So it's not a benign condition at all. And this is something that we tend to do in psychiatry. We think that we look at diagnosis or studies longitudinally. But even if you think of the most common way of analyzing longitudinal data, Kaplan-Meier, to an event, that's actually just two points in time here. And how long does it take to this patient to relapse? What's actually more important is what happens within. Let's say if a patient is well within that year and doesn't relapse, what do we mean by well? And well should mean absence of subsyndromal symptoms. And that is a challenge with bipolar disorder. Even if we keep patients in remission, they have subsyndromal symptoms, and subsyndromal symptoms affect what matters to patients, functioning. If we look at the symptoms that we have in each of the syndromes, we tend to think that if you look at the depressive symptoms, every single of these symptoms, you have a higher prevalence than in mania, which is again talking about the severity. Even having arguments. We usually think of having arguments when a patient is in an irritable state, but actually, as you can see, patients with depression, and this is bipolar depression, we're focusing on bipolar depression, have a higher prevalence of all the different symptoms, including one that we usually associate with mania, which is arguing. Misdiagnosis. It is the most common, well, I shouldn't say the, one of the most common diagnoses in psychiatry that is misdiagnosed. So this is DSM-5, and it is inter-rater reliability, and of course, you want an inter-rater reliability of one. Anything under one is not ideal. So what you can see in 0.56, that is the inter-rater reliability of mania. So it's better than depression, but look at, the terms are missing there. That's why I'm pointing out to the, 0.4 is the inter-rater reliability for bipolar depression. It's really not good at all. So it's hard to diagnose, even when you're using a structured diagnostic instrument. So why is it difficult to diagnose? Why is there so much misdiagnosis? Well, especially bipolar II patients with bipolar disorder suffer from anasognosia. They don't know if they were well or not, especially bipolar II. That's when I, when the first meeting that I have with my patients with bipolar disorder, what I tell them is, in order for me to do my job, you need to help me by giving me permission to talk to your significant other. Number one, to get the history, and then number two, of course, to see the course of illness. And bipolar II, most patients, they were not aware. So I see some young folks, including some of our residents here. The key thing, when you're doing a structured diagnostic interview or first interview, make sure that you have a family member or a significant other around to get that history to rule out bipolar II over major depression. So the major misdiagnosis or confounders, confounding is that gets underway. Of course, unipolar depression is the one that we need to rule out. Substance abuse makes making the precise diagnosis more challenging. Schizophrenia, borderline, that's another one. Many times, some of us tend to over-diagnose bipolar, but others tend to over-diagnose borderline. And of course, they're very similar because it's instability, impulsivity. So the misdiagnosis is very, very common. And then ADHD and anxiety disorders. So this is, I'm sure you've seen this data many, many, many times. And that's because it's great data. It's information taken by patients, as we heard many times. It takes more than 10 years. This is the Hirschfeld study with the MNDEA. More than 10 years to get diagnosed. And as you can see at the very top, the most common misdiagnosis is unipolar disorder. But as you can see, borderline is also there. And this is also from Hirschfeld. So these are patients who were treated and my first diagnosis was major depression. And then when they were screened and the structure interview was done, 20% of them, actually the diagnosis was incorrect. It should have been bipolar depression as opposed to unipolar depression. So 30% of depressed patients suffer from bipolar depression as opposed to major depression. This is actually quite an interesting study by Sharma. And so they looked at patients. And this is using the SCID. And as you can see, they had the first reevaluation, 35% actually had the real diagnosis was bipolar depression. But then on your right is the more interesting diagram that even within a year, you see more patients that were initially diagnosed as major depression. They were re-diagnosed, actually 60% of them, the diagnosis was changed. So good practice in psychiatry to do longitudinal as opposed to a cross-sectional diagnosis because the condition, of course, does change. This is, again, a similar study, unipolar. And when they're interviewed again, and this is with DSM-IV, they had bipolar too. Then there's another interesting concept, pseudo-unipolar, patients who had depression but then were followed by hypomanic episodes, so they were really bipolar. So how to make the differential diagnosis and the executive summary. We don't have biomarkers, right? So how can we do it? Well, DSM-V, and that's the language that we speak, we make the diagnosis retrospectively. If the patient in front of you, they're identical according to DSM-V, major depression from bipolar depression. So you need to retrospectively make the diagnosis of mania and hypomania. Now, this is a very interesting study in terms of progression, and this is really good for DSM-V because you have the three terms. So if you have more than three terms, items rather, then you make a diagnosis of major depression. But if it's less than three, you don't. Does that matter or not? Well, actually, it does because, as you can see, those who had more than three symptoms, as you can see, manic symptoms, when they, as time went by, and this is 30 years. If you want to do the math, 1,500 weeks is 30 years. So the changes happen actually within the first three years. So actually, when you are assessing your patient with major depression, make sure that you look for mixed features. And if you have two or three mixed features, keep a close eye on that patient because the chances of that patient really being bipolar depression does increase. So this is important information. Symptoms that are present, high prevalence in each of the two syndromes. In psychiatry, we don't have illnesses because we don't know the etiology, so we have syndromes. So as you can see, for bipolar depression, you have inner tension, pessimistic thoughts, suicidal thoughts, and for unipolar, sadness and reduced sleep. So there's a number of studies that have looked at specific symptoms. But again, they were not included in DSM-5. So key things. I always say that if I have just one question to ask one of my patients with, say, bipolar depression, and I just have one question, the question that I would choose is family history of bipolar disorder. Okay, so make sure, residents, that you never forget that. Any patient with depression, always ask, is there a family history of bipolar disorder in your family? Earlier onset of illness, that would be number two. Earlier onset, and this is for depression, younger age in bipolar depression compared to major depression. And then the other one you see in red at the bottom, TRD. So we all have treatment-resistant depression clinics. The main thing to rule out is bipolar depression. And many times, these patients have been diagnosed in the absence of collateral information. So it's just simple getting more information. So these are other things that you can look at. Now, this is the collaborative study of depression that took place in the last century. Still quite valuable, quite valuable data. And as you can see, patients with bipolar II spent really most of the time depressed. And this is, again, longitudinal. It's not number of episodes, it's through time. Most of the time they spent depressed. This is actually an interesting one. This was one of the NIMH clinical trials. So then an investigator, well-trained, did a skit on the patients, and then a second investigator from another group did it twice, getting information from a family member. And the diagnosis increased times, too. So here's the evidence of what I was just mentioning. Comorbidities, we've mentioned the comorbidities before. Let me now talk about course of illness. How are we doing with time? Need to make sure that I don't take time away from you folks. Sounds good, sounds good. Okay, so this is another key thing in terms of history. Make sure that you ask what was the type of the first episode, okay? If it was depression, they're going to have a predominant course. That's two-thirds of the time. So this is important information. And there's been a number of studies that have replicated this finding. So this is based on the initial presentation. Again, if they have substance abuse, younger age, in terms of a depression, that will predict that it's going to be bipolar depression. This is a study of our McLean first episode cohort. And these were patients with first episode mania. So we collected data in terms of mixed features. And those patients who had mixed features, and again, this is mania. So mixed features, the opposite pole of depression. Those who had mixed features, as you can see, relapse into depression. So when you have mania, and of course, many times in treatment of long-term conditions, you need to select maintenance treatment. So you have your patient who had mania, and then you need to find out if they were mixed features. So rather than electing a maintenance treatment that is great for preventing mania, let's say, but is not great in preventing depression. So what would be a good medication to prevent depression? Flammatrigine, but not for the prevention of mania. So based on the last episode, you can make your decisions. I am going to now ask our colleagues to come in. We will start with Gustavo or Leonardo, Leonardo Ton. Well, good afternoon and thanks to Mauricio for the organization of this symposium and also for inviting me. I will continue on bipolar depression and also on the differences here, okay? And also on the difference between bipolar depression, bipolar disorder two and bipolar disorder one. No relevant financial relationships. People who have worked on this project are Rosvald De Serrini and then other friends and colleagues in Italy. As an introduction, and just to continue what Maurizio was showing about depression in bipolar disorder patients. These are eight studies on bipolar depression, bipolar disorder type one treated. And as you can see, 45% of the illness that they have, despite being treated, is depression. And depression is actually three times more frequent than mania and hypomania. So depression is actually the most important issue in treatment and in the evaluation of bipolar depressions. For bipolar two, I put down very, very short historical background. St. Kraepelin had a broad concept of manic depressive insanity. Actually, there is a recent study showing that more or less Kraepelin believed in dimensional idea of the bipolar disorder. In around the 1970s, Danner actually decided that there was a bipolar two disorder without mania. And he took hypomania from Emmanuel Mendel, an old doctor from 1881, which was actually taken later by Carl Jung. But that's another story, I don't want to get into it. And then in the DSM-3-R, the bipolar two disorder was described as a boundary between bipolar one and major depressive disorder. Hypomania was a specifier for major depressive disorder. And it was a new diagnosis within the bipolar spectrum. Then, with the last DSM, the DSM-5, diagnosis of bipolar two is there. And also in the DSM-5-TR, with different codes. But bipolar two disorder does not have the same specifiers as bipolar one disorder, which is actually kind of tricky in a diagnosis because you cannot see anything about the intensity of depression, whether they're remitting, and the severity of episodes, or the presence of psychotic features or mixed features. That is why we decided that we wanted to do something else in this field. So bipolar two, as Maritza was reminding, is a difficult syndrome to identify and distinguish from a major depressive disorder. One of the reasons is that hypomania is not easily recognized. And patients who have overspending and sleeping three hours per night, or maybe cheating on their significant others, do not really recognize that as hypomania. But they say that they were just absolutely fine, and probably also a lot of fun. And also, so we know that the difficulty, I mean, we're talking about all this because it's very difficult to treat bipolar depression. And so we're going to do, we're going to say something about this. And also, Gustavo Vasquez is going to be, he's going to enter more the problem with the treatment of bipolar disorder. Now there are two views about the idea of bipolar one and bipolar two. One is that bipolar two, as I was saying, is an expression of a bipolar spectrum. And not only this, but the Australian and New Zealand College of Psychiatrists decided to get rid of the diagnosis of bipolar two and decided that there is bipolar disorder and major depressive disorder. They're not followed by all other colleagues. And instead, still in Australia, Parker says that bipolar two has to be considered an independent diagnosis. And so we started our own study just to see whether we could say that the two syndromes are quite different. So we examined subjects, I mean, almost 1,400 subjects that I have followed for almost four years. And bipolar one was more or less 50%, women more or less 50%. The mean age, 43 years. With bipolar two, a little more as a general proportion, more women. And of course, the mean age is older because usually bipolar two patients are seen later in their life. As a sort of a byproduct of our study, we had this type of regression and see if the diagnosis of bipolar two has changed over four years. These are all my patients. And actually, it has changed, and it's changed significantly. Now, I make much more diagnosis of bipolar two than before, probably because I have learned that kind of third degree interrogation with patients to try to understand whether they had some kind of hypomania in the past, and so trying to explain what hypomania is, and it can be considered real hypomania. So what we have found as a result, we found that actually, bipolar two are different for many factors. We examined the demographic factors and we saw that bipolar two persons tend to be more women, older age, better educated, more employed, higher socioeconomic status, more married, and having more children. So there is something different in demographic factors and we looked at the clinical factors and we saw that they tend to be older at onset and we know that, that's very common finding. Older also at the first symptoms and treatment, they tend to wait until the symptoms become clinically relevant in order to look for treatment. Family history and mood disorder. It's interesting because bipolar two patients tend to have more family history of mood disorder but not of bipolar disorder, but this is complicated because considering the collection of information about family history is mainly retrospective. Certainly there is a lot of misclassification and it's very complicated to reach a good diagnosis of bipolar disorder in subjects who are not directly assessed. Then they tend to have more cyclothymic temperament, more occurring anxiety disorder, ADHD, and medical illnesses, less BMI, so they tend to be thinner, and less seasonal variations. Well, and of course the BMI is actually lower because they do not take a lot of antipsychotics as the patients with bipolar one disorders. Less seasonal variations and less use of substances and cigarette smoking. So they're, in a way, in some way they behave better, so to speak, than patients with bipolar one disorder. Also for suicidality, they tend to have more suicidal ideation but less violent suicidal behavior, which we know are more characteristics of patients with bipolar type one. For morbidities, more depression as Maurizio was showing, and we saw that it's much more likely that the first episode is more likely depressive, longer duration of the episodes, and therefore more time depressed and more predominant depression. Less mixed first episode, more switch risk and more rapid cycling, which is for one reason that I will show later. More depression hypomania interval course sequence. I mean, this course sequence is something that I will describe a little later, and it indicates that bipolar disorders do not come always with the same type of cycling. I mean, some patients start with a mania followed by the depression, and some others start with a depression followed by mania. And that actually, it means something in terms of treatment, and I will discuss that later. Also, examining the results of the rating, of the scores of the rating scales, bipolar disorder, patients with bipolar disorder do tend to have higher depression scores, anxiety scores, but lower mood disorder questionnaire, which means lower hypomania, and also lower young mania rating scale scores, which means that at the intake, they tend to be less hypomanic. I mean, meta-analysis of mood switches actually is in contradiction from what we saw, meaning more switch in bipolar II disorders, and instead, meta-analysis on 10 studies showed that switches are more likely in patients with bipolar I disorder. Well, it could be. Anyway, it's not in our data. But we also looked at the different scores at the Hamilton Depression Rating Scales, and in patients with bipolar disorder II, we found that they were more depressed, more guilty, feelings of guilt, more suicidal ideation, early insomnia, and early awakening, less psychomotor retardation, more agitation, more anxiety, less appetite, which means also more weight loss, more hypochondriasis, and less paranoid feelings. So even from a simple collection of the Hamilton Depression Rating Scale, we can have an idea about the possible differentiation of a depression belonging to a bipolar depressive disorder type I or type II, although this is not really feasible when you see one patient, because you should have, I mean, you should see probably many patients. I'm getting to some of the treatments. And again, from the same study, we found that bipolar patients were less treated with lithium, and when treated with lithium with a lower dose, which makes a lot of sense, as expected, and also, as expected, we found that they were using, that they were taking more antidepressants and more benzodiazepines, and less antipsychotics, which also, as expected. The CANMET, I don't know, actually, I don't think that this is the latest version of the CANMET 2018, probably, is it? Okay, well, it suggests that, I mean, you know how it works, I mean, the guideline based on the empirical, all the studies together, and so they found that for the treatments of acute bipolar depression, acute bipolar depression, the first choice is in monotherapy, lamotrigine, lithium, luracidone, and quetiapine. As a combined therapy, lamotrigine, adjunct to possibly an antidepressant, luracidone plus lithium and valproate, and as a second choice, as a monotherapy, they would suggest valproate, ECT, cariprasine, we should never forget that ECT could be extremely important, especially in very severe depressions, and then as combined therapy, the SSRI or bupropion as adjunctive to a mood stabilizer, and the combination of lanzapine and fluoxetine, so we could never err on this side of the guidelines. Despite all this, a study based on 1,200 patients in Europe shows that most of the patients with acute bipolar depression are prescribed with antidepressants, secondarily with mood stabilizers and antipsychotics, and lastly with lithium, and we know that lithium is not much used anyway. We also conducted a meta-analysis on placebo-controlled antidepressant trial plus or minus mood stabilizers, and still, we saw that the use of antidepressants in no matter what, combined, not combined with a mood stabilizer could be also quite effective, and so it's really difficult not to use antidepressants even with a bipolar depression, and for the medicines that are most used, quetiapine is certainly, I mean, beats any other possible treatment. I don't know about the last treatment, like cariprazine or brexpiprazole, but I mean, according to this study, which is not so recent, it's 2010, quetiapine was the best treatment at the time. So in a more recent study, the approved indication for bipolar depression was only for olanzapine plus fluoxetine, quetiapine and ketamine, and Gustavo Vasquez is going to speak about ketamine, so I'm not gonna say anything about it, and for prophylaxis, lithium and lamotrigine, but we know that lamotrigine is not as good as an antimanic agent, so it's useful only for recurrences of depression. Yes, I wanted to say something about a course sequence. What we mean with course sequence, I mean, actually, it's an idea which started with Koukoupoulos in the 70s, but the last paper that we wrote was in 2013, so that there are two main courses of bipolar disorder patients, one with mania, depression, and a free interval, and this is especially frequent. 70% of the cases are found in patients with bipolar disorder type one, and then there is the other one, which is depression, mania, and interval, which is actually present in 2 3rds of the cases with bipolar II patients, so they're quite different in terms of type of course sequence. So when we treat depression in those two types of sequences, the depression with the first one, with the MDI course, can be treated stopping the antipsychotics used for the treatment of mania and adding a brief treatment with an antidepressant because the chance that the person might have a switch is actually a little later in time. It could be maybe a year later, so I mean, a short treatment can be quite safe, and instead for when you have a patient with depression and mania, it's always very important to be careful about the possible induction of hypomania with antidepressant, and then probably developing into rapid cycling, so how to detect this type of course sequence. Actually, patients can reply to this kind of question very, very easily because if the question is asked in direct way, I mean, do you know that whenever you had your depression that was followed by hypomania, or maybe when you were treated with an antidepressant, do you remember if you had hypomania afterwards? So they know very, very well, and it's easy, it is another, well, it's another factor that can be used for a better treatment. So at this point, is the separation between bipolar II and bipolar I justified? We think that there are different demographic and clinical factor which are helpful to separate the two syndromes. The separation is useful in line with precision psychiatry because if we know that patients can actually treat, they can be treated or respond better to a certain type of treatment, it's more precise, of course. On the other hand, as Maurizio was mentioning before, bipolar II disorder is not less severe form of bipolar I, especially because the depressive morbidity is actually more intense, more severe, and the rating scales for depression tend to have a higher score. Also, there is a recent study showing that there is a genomic difference between bipolar II and bipolar I, with bipolar I looking much closer to a major depressive disorder, which also makes a lot of sense. On the other hand, the dimensional model of bipolar disorder reflects certainly much, much better the variability of a complex illness. We can discuss for hours about how a mania could be diagnosed as mania or hypomania, and what is the difference, I mean, which, I mean, actually the differences are, I mean, the patient is doing, is behaving in a more, in a stranger way, but it's not really quite easy to define even the difference between mania and hypomania. So it means that the dimensional approach should be the right one, but it's also very difficult to use, because a categorical model is useful for genomic study, but also for clinical use, scientific communication. It's almost impossible to communicate a dimension of, the dimension of a bipolar disorder, I mean, because, I mean, it's very, very difficult to express, well, it's difficult, quantitatively, how to measure the hypomania or the mania. So it makes a lot of sense that we keep the categories separated. For this, for these reasons, we, in our, in the paper that we submitted, we not so humbly proposed two major differences. One, which is rather simple, but the use of Arabic number one and two to correspond to the spoken language, because we use the Roman numbers, which actually means first and second. Well, we should probably use one and two as a Arabic number. And then, and then I think that the specifier that we use in bipolar type one disorder, like type of current or last episode, illness severity and remission state should be used also for bipolar two disorders. I mean, I tend to use it when I write down the diagnosis of my patients. As conclusions, so we found that there are more bipolar two subjects, and we know this because being a less severe syndrome, it's much more likely that it's more present in the population. Initial diagnosis and treatment is later in bipolar two subjects, because I mean, of course, in bipolar one subjects, the severity of the, especially of the mood elevation would require almost an immediate treatment. There is more depression during all course of the illness in bipolar two disorder. The first episode, more time depressed and predominant depression. More cyclothymic temperament, more rapid cycling, less seasonal variation. Though all these factors should indicate that we are speaking of a more chaotic course of the disease, and instead, in bipolar one disorder, we found quite often a rather precise and repetitive type of course. There is more favorable functioning in bipolar two patients, more education, better employed, I mean, better income, and being married with kids. Also, more antidepressants, less antipsychotic, and less lithium, as expected. And a new proposal for the new DSM revision, which has not been taken so far, for a more precise diagnosis of bipolar two disorder. Thank you. Thank you, Leonardo. Our next presenter is Gustavo Vasquez. So I asked Gustavo, how should I introduce you? And he said, well, let's just say that we're friends. But actually, we're more than that. As we would say, we're like hermanos or fratelos, as Leonardo would say. Because we have the same mentor, Ross Baldessarini. So, and I had mentioned to them, let's dedicate this presentation to Ross that has been a big influence. So, mi hermano, my friend, Gustavo Vasquez. Thank you. Thank you, Mauricio, very much for your introduction and for presenting me. Of course, that's the only reason I'm here, because he's the chair, and he invited me. Anyways, so I'm going to talk about treatment, and I'm going to talk, Leonardo already talked about different treatments for bipolar, especially bipolar I and II. But I'm going to introduce a novelty treatment, that is, that is ketamine. Probably you already know about this. We have to say that actually it's an off-label treatment, but we're going to present some results from our clinic. This is the disclosures from the last three years. I would say that there is no disclosure on this. Ketamine is off patents like 30 years ago, so there's no pharmaceutical competencies here. But there is a lot of money coming from research grants to correspond with this presentation. So probably you know that the antidepressants are usually using, the oral antidepressants works on neurotransmitters that are affecting or changing serotonin, dopamine, adrenaline, noradrenaline. And they are effective, quite effective for some patients, but not for all. So most of the patients that have actually severe depression are less responding to these treatments. So really we need different medication. I think I'm very hopeful because there is a lot of new compounds with different mechanisms of action coming to research in the pipeline, as they call it. So I'm really very hopeful on the results of that studies. But really we need different medications with different mechanisms of action in order to help those patients that are not responding to our traditional antidepressants. You probably know that at least one third of the patient with MDD are considered treatment-resistant depression. That means that they have taken two different antidepressants for enough time, enough dose. But in the case of bipolar depression, that is the topic of our symposium here, this is actually worse. We have found studies, again, with Leonardo and with Dr. Roswell-Desarini, that treatment-resistant depression in bipolar disorder is two times more prevalent than unipolar or MDD. Additionally, you know that all patients have to wait a certain number of weeks. Sometimes we said, like, very confident it's going to be around four weeks, but most of the patients, six or eight weeks, have to wait. And it's still, you know, taking the medications, going with all the struggles of the side effects all that time, plus their disease, to get the response, hopefully, they're going to have with the medication. So we really need not only different mechanism of action medications, but also medications that can work fast than the ones we have now. So here comes ketamine. Actually, I was a bit pushed by Dr. Carlos Zarate, that's working in the National Institute of Mental Health, and very colleague and friend of Mauricio, too, to research on ketamine in depression. As you know, ketamine is an antagonist of the receptor NMDA, and really have a different mechanism of action in many sense. It's not only the mechanism of actions over the glutamatergic system, but it seems that there are other neurotransmitters that are also implicated in the mechanism of action. Most of them are related with not only the changes on the receptors and the neurotransmitter, but also with the rapid effect they have on neuroplasticity, on our neurons. Most of the research we have from ketamine in depression are estimated response rate around 50 to 60% in those patients that have TRD as a main diagnosis. This is from just a colleague and one of our students that published this study on the mechanism of action of ketamine. As you can see, it's very intricate. It's very complicated. It affects a lot of, you know, we have like hypotheses on how it's working, but we really don't know how it works, but it really affects a lot of different points, not only in the neurons, but also in the glia and other cells in our brain, in our CNS, you know, our brain. So one of the first really interesting study that came in the literature about ketamine was its effects on suicide ideation. And this is coming from the group of Yale and Wilkinson, 2017. And you can see here that only one infusion of ketamine reduced the suicide ideation significantly in patients with suicide ideation. And this lasts for at least seven days, just from the very, very first day. So this is quite interesting, especially that, as it was mentioned, suicide should be and is one of our main concerns. So this is really, really interesting. The other thing that I should underscore on ketamine treatment is that it depends on the number of infusions. So the more infusions received, the better chances you are going to have to respond. So you can see here in the middle, in the graph in the middle, that the more infusions you are receiving, the less severity on the Montgomery scale you are going to have. This is also important, the last graph on your right, that some patients are responding very early, but some of them are responding at the end. So they are called later responders. So this is very important because once patients are getting into the step of their treatment, it's almost the last resort. So we have to be very careful on the number of treatments, and it's recommended to give at least eight infusions over a course of one month, twice a week, to find a real response in these cases. So this is also a very important point. Regarding doses, this is a very elegant study by Faber, Mauricio Faber from Boston. And you can see here that despite there are different protocols, the most useful one is usually 0.5 milligrams per kilo. So usually the infusions is tailored to the weight of the patient. I think this is also very important in regards to response. So the most beneficial in terms of risks and benefits is 0.5 milligrams per kilo. And that's the one that most of the clinics and institutions are using for the treatment of depression. Again, as I start this talk, this is off-label treatment. So it means that it's not approved by any health association, any entity in any government around the world. But we have some support from clinical guidelines. I think that Dr. Roger McIntyre was presenting on the first one, this international consensus around the use of ketamine, published in the American Journal. Of course, there is a Canadian version from CanMath, led by Jennifer Swanson. So we have at least some background from the academia to help us on decide which patient would be the best fit for the treatment, which are the most difficult side effects we can encounter and how we can keep on the treatment. So there is some help on this regard, but again, this is an off-label treatment. With one of our residents, we made these systematic reviews and networked meta-analysis. One of them, the first one, was actually published in the Journal of Affective Disorders. That is the editor-in-chief, Dr. Soares is here, on monotherapies and combination treatments. That is the most common treatment for bipolar depression. And what they defined, we found that actually ketamine was, even though there is only two trials, RCTs, is the most powerful, the more effective treatment compared to the other ones on resolving patients that are struggling with depressive symptoms. The first study was published just 12 years ago by Diaz-Granados from the lab of Dr. Sarate. And again, this is only one infusion, and you can see that just from the very beginning in the first 40 minutes, there is a significant change on the mood, on the severity, according to the Montgomery scale, on the mood of the patient that is sustainable up to seven days. And then it's losing efficacy, and actually, it doesn't differentiate from the placebo. But this was a very important signal that ketamine could work for bipolar depression. Since then, we have just six studies. Most of them are single dose, so they try the patients with only one infusion. Numbers, as you can see, are very low, open label, so you have 17 patients, 15 patients. There is only one study that actually treated the patients with a series of infusions that goes up to six infusions. But all the rest are, again, numbers are very low, and there are only one infusion. So what I'm going to present now is the results we have from our clinic in Ontario. This is a public hospital, so we don't have any kind of commercial interest in this regard. This is not a private clinic. So we are providing, we are the first and only so far clinic in Ontario in one of the largest provinces in Canada, providing ketamine for free for patients with TRD. And what I'm showing now is the result we have so far on patients that are having bipolar depression, and there are treatment-resistant depressive patients. So again, I think even though the numbers are very low, but the age is quite similar. It was presented by Dr. Zondo. Females a bit more than males. You can see that many patients already fail ECT. They have treated with ECT before. The Montgomery scores is in line with severe depression. And we have most of the patients with bipolar NOS and bipolar II. Number of medications the patients were taking is 3.8. So this is the demographic data of the patients, and what I'm going to show now is the results of this study. Again, this is open level. We couldn't blind the patients. We couldn't do any kind of blinding or using an active comparator here, but it's a prospective study. Here, there is a lot of work made by research assistant, by medical student, nurses, et cetera, et cetera. So you can see here that, as mentioned, the Montgomery scale is just ranking a severe depression, and after one hour after the treatment was done, you can see there is a significant difference in the Montgomery that is sustainable until the end of the treatment, at the end of the fourth week. Some people ask about ketamine. Well, it's psychedelic, it's drug abuse, it's something that is going to put you high, so it's not really relieving depression, but it's something different. So I'm putting here the difference in the Montgomery in every item of the Montgomery scale. The percentage of decrease from the first treatment in the first week, that is in blue, and at the end of the treatment, that is in yellow. And as you can see, there is a change in all and every significant item here, that is the time items of the Montgomery. So it's really a medication that is producing a significant change in every aspect of the scale. We also use the Sheehan, this is a drug, the Sheehan disability scales, as probably you know is one of the most useful tools for assessing functionality among patients. And you can see that also, again, it makes sense if you are getting better from depression, it's also making sense that you are performing better, functionality is improving, so you can see here that from the first day of the treatment until the end of the treatment, you have a significant decrease in the three areas that is the Sheehan disability scale measuring, that is work, school, academic, social, and family. So side effects, that is very worrisome for many because this is, again, a drug with potential abuse and can have many significant issues in that regard. So first of all, we have to say that we are using 0.5 millions per kilo, that is infused over 40 minutes, okay? So that is, patient is working 100 kilos, that means that it's going to receive 50 millions over 40 minutes. In anesthesia, they are using between 300 and 500 millions to put someone to sleep, so this is a very, very low dose and is just given to the patient in 40 minutes, very, very slowly. And of course, the drug, the patients or the subjects that are abusing ketamine in the street as recreational use, the dose is much higher than that. So it's very difficult that the patient is going to have what they are looking for in the streets. But anyways, we have to make sure that the patients are safe, so first of all, I will say that in the, on the right, you can see the change in the young mania rating scale, just checking for potential hypomania or mania, and you can see that it was stable along the treatment. And the VPRS, that is the Brief Psychiatric Rating Scale, you can see that actually the severity is decreasing. So that is also very, very helpful to, for our patients and for us, that the treatment is not really damaging or increasing the psychopathology of our patients. What is also very important to discuss is that the more treatment you receive, the less dissociative effects you are going to have. This is usually measured with a, when the scale is called CATS, it's a scale that was designed for PTSD. And in the subsection, there are three subsections. In the subsection of dissociation, you can see that there is 46% of the patients having some dissociative symptom in the first treatment, but this is decreasing along the treatment. So the more infusion the patient have, the less of these dissociative effects the patient are going to have. And it's very important for us to explain the patient because patients are usually saying that the treatment is not working as well because they're not feeling the same during the treatment. So they feel that maybe they're losing, you know, the efficacy of the antidepressant effect because they're not feeling exactly the same, but this is actually something that is happening for all patients. So gradually, this side effect is decreasing. We have to check, as you probably know, on the heart rate and also the blood pressure because as a physiologic effect of ketamine, there is an increase around 10 to 20% of the baseline. So we have to monitor that on the patients too, especially at baseline. So we are making diagnosis of a lot of hypertension, you know, that have been undiagnosed until then. But once the patient is treated, the family doctor and the blood pressure is under control, the patients can go ahead with the treatment without any problem. So again, and I'm just almost finished, just the two final slides to have some time for the discussion. I think that one of the most interesting part of this treatment is the effects it have on suicide. And just to make a comparison here, I put some of our patients that are just fulfilling criteria of MDD, of unipolar depression, and you can see that both in bipolar and unipolar, the decrease on the suicide ideation is significant very, very quickly. And this actually could help a lot of us and a lot of patients for sure, and their families on the treatment, adequate treatment of suicide. Another finding that is still quite debatable or controversial is if there is an independent effect over suicide by ketamine compared to clinical change on the severity of depression. That means that it seems that at least in our small sample, this is combining bipolar and unipolar patients, we are seeing that patients, even they don't have response, clinical response to the depressant effect, they still have a significant decrease on the suicide ideation after one hour of the treatment. So I think that's also something that should be deeply studied as it could help a lot of our patients and their families. So finally, we're just going to open for discussion now, just to conclude that ketamine is a rapid-acting antidepressant which sustains efficacy over time. This is the main point that most of colleagues are asking, okay? But this actually doesn't work because you have to give one treatment, and then in one week or 10 days, the treatment have stopped working, so you have to give another one. So what I'm asking these colleagues is just name one of our treatments that you stop it, and then you wait seven, 10 days, and the patient is still doing well. So most of our treatment, unfortunately, most of our diseases we are treating are chronic, long-term, and we have to keep on the treatment to have the results, and this is one of the treatments. What is important to mention here, I was just talking about acute treatment, is that we are maintaining patients on ketamine that are coming to the clinic once every two, three, or even every four weeks to receive one treatment, and the patients are doing well. Another important point to mention here, it is usually more effective if you are combining the treatment with oral antidepressants or mood stabilizers or a typical antipsychotic as a combination of an oral medication, but we also have some patients that, because of side effects, they don't want to take oral medications and are just treating in monotherapy with ketamine, and some of them are doing quite well. Ketamine induces rapid and significant decrease of suicidal ideation within one hour, so I think this is very important, especially our colleagues and us that work in the emergency department to provide the treatment that effectively and very quickly and strongly change suicidal ideation for a different follow-up with shorter length on the stay in acute units. Ketamine antisuicidal effects were independent of the patient mood response. Again, this is controversial. There are studies going on, but it could be also a very good finding if it's supported by other studies, and of course, as usual, long-term benefits and risks remain controversial because this is quite new, and the number of patients are growing gradually, but the number of patients that really screen and follow-up in academic centers are very low, so we are just finding the results over the way. We are just transitioning. So this is some of our colleagues, students, PhD students, master's students, residents that have helped to produce most of this information. I'm going to stop here and open for the discussion. Thank you very much. So now we move to the discussion. We have Dr. Jair Soares, Jair is Chair at the University of Houston and Editor-in-Chief of Journal of Affective Disorders. Jair. Thank you. Well, good afternoon, everyone. I'm honored to be here. I actually get the easiest part, the easiest job here tonight, after these brilliant expositions by these three distinguished gentlemen, there is probably not much that I can add, you know, that they haven't already explained so well. Well, I, when I start by first, so Professor Towin mentioned Professor Ross Baldessarini from Harvard University as a very influential figure in this entire field of bipolar disorder. I was never mentored by him, but was certainly very influenced by his work. And this past Friday, Mauricio was there. We are both part of the American Chairs of Psychiatry Association. And we got to present our Lifetime Achievement Award to Professor Baldessarini. So that was a very special moment. And you know, those are three very distinguished professors that were all mentored by him. So that is a sign of his great influence in our field. So I want to honor him for that. The, so Mauricio Towin gave us a really nice overview for the dimension of this, you know, important problem. As we all know, it's a very chronic condition, and the outcomes are really suboptimal. You know, the studies that look into that, it seems like some residual depression. You know, since depression is a, the prevailing flavor there across both bipolar I and bipolar II. It seems like some level of residual depression is a big part of why these folks improve, but can't really get back to functioning the way they used to. Another important area that's been researched quite a bit, you know, the past few years is really this notion that many of these patients will have detectable cognitive impairment. And the more chronic they've been, the more cognitive impairment we are going to find. And as the symptoms, the depression and hypomania are under better control, of course, neurocognition improves, but most likely not all the way back to whatever the baseline might have been. So that's another very important reason for much of the disability that these folks have. So we move down to Leonardo Tondo's excellent presentation, essentially showing us how hard it is to distinguish and diagnose these different subtypes. Well, thankfully, in many instances, they both respond to, you know, by largely the same treatments, bipolar I and bipolar II. But Professor Tondo's presentation really, you know, illustrates to us how hard it is based on an interview that is often, you know, retrospective and the clinician may not have seen, you know, the hypomanic presentation. So just based on the patient's recollection and sometimes on any corroborating information we might be able to obtain from the family, that's often a diagnose that we may miss or alternatively we may actually overuse, you know. I see all the time patients with an anxious, depressive presentation, you know, if they have some mixed, you know, symptoms to their presentation, that I do believe that we over diagnose that too. I mean, we miss the hypomania and therefore are labeling as unipolar, like MDD patients who are bipolar type II. But I also believe that in many instances, because the person has some anxiety alongside with the depression, we may be calling bipolar type II folks where, you know, if you take a close look, that's not really well established there and that may not be the correct diagnose for them. So last, Professor Vazquez, Gustavo Vazquez, really illustrated to us a new treatment that is, you know, coming up strong with quite a bit of evidence that it helps not only MDD patients when they are depressed, but also patients with bipolar disorder during the depressive phase. It really illustrates the need for more efficacious treatments for these severely ill folks. So ketamine and escetamine have come to the scene the past few years. We've also seen some new atypical antipsychotics that have gotten, you know, approvals and an important role. Many of these folks, as we clinicians know, end up needing a combination of medications since we can't really control the symptoms well with the, you know, monotherapy, which is often, you know, what we try first. So we have a long way to go and really need to continue to step up our science to try to find better ways to help these folks because the disability is very prevalent and it's everywhere, you know, you look essentially. So when I'm treating patients with bipolar disorder, I like to, I tell them, I say, look, for us to help you get well and stay well, let's think of what it will take in terms of three thirds. And I tell them, look, the first third, let's see what we can get from the medications. You know, medications help as long as, you know, they are doing more good than bad. Essentially they're helping and the side effects are tolerable. And where, you know, you will, I stick with them. So let's work on that, but that's not going to be a miracle and that's not all. The next third is really, you know, what psychosocial intervention, psychotherapy can help you with. And when we look at that, where there is really more evidence, I mean, the most evidence-based type of psychotherapy for mood disorders, bipolar disorder is really CBT, you know, variations of cognitive and behavioral therapy, lots of evidence that they really make a difference. They work. More recently we've seen also more structured ways to try to help the families, the significant others of the individuals that suffer from bipolar disorder. And that's another very important component of, you know, this second third that I tell my patients with the psychosocial interventions. The final one, I tell them, look, this is where you can really empower yourself and things you can do to live a healthier life. So the final third, the third third, is really around lifestyle. And giving yourself enough sleep and understanding that things that people who don't have bipolar disorder, that they can do and get away with, someone who suffers from bipolar disorder, if they try that, in all likelihood, that's not gonna be the recipe for them to get well and stay well. And like common sense things, like staying away from excessive drinking, use of illegal drugs that may help temporarily, but over time will take a toll and make the mood more labile. And we see that all the time. And the common ones, smoking pot and using other types of stimulants and drugs. Then I also tell them that there is, on the lifestyle part, there is a lot of evidence to show that the same things that are good for the body, they are also good for the brain. So regular exercise, very powerful way to lessen depression, lessen anxiety, and just improve our general wellbeing. It may be hard initially if folks are very depressed, but we can make some progress. We can work with them where gradually, they can get to do more. Diet is an area that is discussed quite a bit. I mean, don't we all believe that a healthy diet is good for our body, is good for the heart? And I strongly believe it is good for the brain. It's hard to, I mean, there's not a whole lot of evidence to say that a certain diet, if followed, would result in better outcomes. I mean, that is still to be established out there. But generally speaking, the same way that we believe that a healthy diet is gonna keep the heart healthier longer it's gonna keep the brain healthier longer as well. And that's another important point for us to emphasize to our patients. But this is a chronic condition. We don't have a cure. There is generally not a quick fix. So us keeping, I think keeping that into perspective and keeping a proactive but also optimistic type of attitude and approach to our families and our patients and their families, I think that's very, very important for their overall recovery. Well, so that's what I wanted to say to, just like I said, there's not much that I can add to the brilliant expositions already given here today. We do have 15 minutes remaining for any questions. So any questions from the floor, we'll be glad to take them. Is this working? Hello. Yeah, go ahead. Yeah, thanks so much for the wonderful presentation. I'm excited to ask this question. So would all agree that apathy lingers in our patients when we're managing bipolar one or two. And I always ask my senior colleagues, like how do you tackle apathy? And apathy usually patients would refer to it as a numbness and that's like they can't experience sadness, I mean, negativity or positivity. Like something happens in your life, they do not have any emotion to express, I mean, experience it or express how they're feeling. Now I've heard people say, oh, you know, with modafinil, you know, they might improve. And I've heard people say they use Wellbutrin. Now I'll cite an example. You have a patient who is on mood stabilizers and maybe they have a comorbid disorder like PTSD or panic disorder. So they're taking an antidepressant alongside the mood disorders. I mean, alongside, yeah, the mood stabilizers. Now they're also receiving CBT. However, they keep coming to you, you know, reporting apathy. And it's concerning, especially when you, sometimes it's even mistaken for depression. You know, your patient is coming back saying, you know, I'm fine, my depressive symptoms are good, but I still can't feel anything. How do you tackle it? What do you use in practice, you know, to be able to help this kind of patients? Now, the second question goes to the last presenter about ketamine. I've been monitoring ketamine for many years and I was kind of disappointed when Spraveto came out and they were like, oh, bipolar wasn't one of the indications. Now the question is, how long have you been using ketamine in your practice and what are the long-term side effects? I mean, what long-term side effects do you envisage, you know, in, you know, administering it to your patients? Thank you. You wanna take that, Gustavo, or Leonardo? So I will start for the last question. So we opened our clinic in September, 2019. So we have been working with treatment on patients with depression, bipolar, unipolar since then. We have more than 1,000 infusions already done. Some of the patients are doing just the accurate treatment and they stay well. Some of them just keep doing the treatment as maintenance. So far, we didn't have any major issue, any major side effects. We are controlling liver function and we are checking, we know about potential addictive, you know, side effects that could come from that. But patients are really not craving. They are not coming, like, asking for increased dose or doing the treatment more frequently. On the opposite, they prefer to come, the stretching, you know, the length of the infusions, because they're feeling well. And we are very flexible on that. Some patients are, again, doing treatment every month, every five weeks, and they're still doing well. So we didn't have, so far, any of those problems. One point I didn't mention, but many of our patients, we are a tertiary clinic service, so many of our patients have tried most of the antidepressants, but not the older ones. So before going to these treatments, we have TMS, ECT, ketamine, esketamine. Before going to those treatment, you should try TCAs or MAO inhibitors. And because of the mechanism of action, you can provide ketamine infusion with patients that are actually taking phenoxyne or tranexypramine. They are taking MAO inhibitors. There is no interaction whatsoever. So that's also very, very important to mention when we are talking about these very complex patients. Let me just mention the first question of the colleague, the whole thing about, I guess, apathy or anhedonia. It's not a condition itself, but there's a lot of interest. And I can tell you, in the pharmacological world, now a number of individuals or a number of groups are focusing on anhedonia. So that's more to come. I must mention that the interest in bipolar depression has really grown in the last few years. In the past, it was sort of forgotten. And I think this has to do a lot with the influence that many of our dear colleagues have had in terms of emphasizing the problems with bipolar depression. But I can tell you, there's a lot of interest in finding more treatments for bipolar depression. Leonardo? I would like to add just a few words about the idea of finding a treatment, I mean a pharmacological treatment for apathy or anhedonia. I think that it's not really possible to target one symptom with a medicine. And I think it's also really bad communication for a patient thinking that there is one symptom and then we can actually have a remedy for that. I mean, anhedonia, apathy maybe should be, you don't know, dealt with in a different way. And so the patients should probably go through some kind of psychotherapy and understand a little better what the meaning is, rather than thinking that it must be a medicine that will probably solve everything. But there are other questions here, so I'll stop here. Next one. Hi, I'm David Asser from the VA Boston system, Harvard Medical School. And I guess no meeting like this would be complete without someone discussing the controversy about the effectiveness of antidepressants in bipolar depression. You did cite a meta-analysis finding some benefit, but there are other meta-analyses that fail to find a benefit. So I would ask this one specific question. What does the panel members think of the study from the STEP-VD study by El Malik and colleagues that found that use of antidepressants in that study tripled the rate of recurrence to depression compared to not having people on an antidepressant added to their mood stabilizer in bipolar disorder? What's your thought about El Malik's study? Thank you for that very controversial question. There is a lot of still, you know, struggle there. I would say that having proven that antidepressants are probably in patients that have a history of rapid cycling to increase it, but also even studies by Nasir Ghaemi, long-term, one year follow-up, it didn't happen in patients that didn't have any history of rapid cycling. What I'm going to say is that, again, I'm trying to repeat it every time this question come around. There are some clinical guidance recommendations. I think the ISVD 2013, most of are there in that paper. They are very, very clinically useful. But I will say that the most important part is to consider the antidepressants as a treatment. So you can do a lot of good with a good treatment if you make a good diagnosis, and you can do a lot of bad with a good treatment with a bad diagnosis. So in that spectrum, we were talking about number of symptoms. I was mentioned, Dr. Choen, on patients with bipolar depression. Most likely, patients that have pure bipolar depression, that means without any symptoms of mania, would probably do better than patients that have three, four, or five symptoms of what is mixed depression. Those cases, antidepressants are going to do worse. So my home-taking message there would be that, again, medications are treatments, and we have to be very careful how we use it and in which presentation we're using. Dr. Tondo have some studies on the use of antidepressants in different types of bipolar, and we can certainly say that, of course, patients with bipolar depression taking antidepressants have more chances to have switch that patients with unipolar depression. If I may add a comment, I remember you, Dr. Rosser, you used to do a lot of studies there. Actually, antidepressants are really not out, we should think about them in the treatment of bipolar depression, they're there. There was a, I'm sure everybody's familiar with the ISBD consensus that the recommendation was, and of course the consensus is the opinion of a number of us that they shouldn't be used on monotherapy, but in fact, the first treatment that was approved for bipolar depression was a combination of an atypical antipsychotic and an antidepressant. So I would say, I wouldn't recommend, I forget, I wouldn't recommend monotherapy, but it's certainly not, antidepressants and monotherapy, but certainly not to forget them as part of the treatment, so they're still there. Any other comments, Gerardo? I would just add that, for instance, if we have time to spend with the patients, and we know that the patient has, because I mean, actually, patients tend to have more or less the same type of cycling, and if we know that the patient has a short depressions rather than long depressions, then it's completely, I mean, the treatment is completely different. And also, another thing that probably is not really much appreciated here in the States is that, I mean, the doses of the antidepressants count a lot, and here, for many reasons, I mean, the doses are, I mean, really much, much higher than the ones that we use in Europe, and probably, I guess that also that makes a difference, and so you can use small doses of antidepressant, and you can have a good effect, and probably it's not enough to have a reaction as a hypermanic reaction, but that hasn't been really studied, this. I totally agree that why we may not wanna use them based on the studies, as part of combination treatment, they are often helpful, and in dealing with more complex case of bipolar disorder, we often have to add those, and it's helpful. We just monitor carefully. Thanks for your comment. The first distinguished speaker mentioned the comorbidity of ADHD in bipolar disorder. I'd like to know how you manage ADHD in a patient with bipolar disorder. The last distinguished speaker mentioned that we should discourage use of port with some of our patients with bipolar disorder. I agree completely with your view, but we're in a very different culture where we have more and more people using port, and patients telling me in my clinic that I've got to medical marijuana, count it down before I sleep. It's what I use for sleep, so I'm finding that more and more challenging. I don't know what to do. I see that every day. I would just tell that I have some patients where they don't improve. The day they finally decide that perhaps port does more bad than good to them, that's when you may see more stability coming. I've seen more than one. It does take a toll. It's also not only port. Most people who are smoking port on a daily basis, they are probably drinking more than they should, and they may be using other things too, so there's that. Mrs. Maria Lucila, good to see you, my friend. Good to see you all, and on behalf of all the patients, including me, many thanks for this very interesting symposium. I just hope, as a patient, that lithium and MAO inhibitors are not going to be forgotten by the young folks I see here. I'm very glad Dr. Voskis still mentioned MAO inhibitors. I've been on every medication that has been mentioned except ketamine, because I haven't been depressed since ketamine came on the market. But for me, MAO inhibitors were the fastest and best solution. I don't see anybody in my self-help groups around the country being on that. Why? That's a very good point. The older folks represented here, myself included, we are not gonna let the young folks not to learn how to use it, but there are different market forces and all sorts of explanations as to why people are using those less and less. Well, first, let me thank you for your transparency. And at the end of the day, if our patients, you're an example, is satisfied with what we're doing, that makes us happy, so thank you for your input. And we'll try not to forget the MAO inhibitors. Lithium, of course, quite an interesting medication that we do forget. Our residents sometimes don't hear enough about lithium, but that's something that should never be forgotten because you should never not try lithium because it is clear that a number of patients respond best and only to lithium, so never forget it. Leonardo knows more about it. What I would just say is that, I mean, Marilu is a pillar of the international group of study on lithium, and every year we get together in different parts of the world, and sometimes, actually, a couple of years ago, we were in Bolivia, where she's from, and she taught us in Bolivia. But anyway, I mean, IGSLI, the International Group of Study on Lithium is a very, very important organization that keeps lithium alive, despite all the attacks that come from the outside. So Marilu is one of the pillars of the institution. 40 years on lithium. Yeah, I would say that we were talking. Thank you. Thank you. Well, I, let me, I wanna continue to, contribute to embarrass Marilu a little, just a little more. So Marilu was the first person who actually invested in me as a clinician scientist. You remember that, Marilu? So Marilu was very involved with NARSA. The first research grant that I ever got was funded by Mrs. Silu over there, so thanks for that, too, Marilu. Yeah. I'm just, sorry, I just want to add something regarding why lithium is not so used. We were talking about Dr. Valzerini, and Dr. Valzerini calls lithium the all-orphan. So there is no marketing behind lithium. So I think that could explain why lithium is so underutilized. Sorry for interrupting. That's okay. I am Linda Hotchkiss, and I'm from Michigan doing collaborative care and working with primary care physicians, seeing patients, and also seeing bipolar patients myself. I have been listening to your discussions, and wonderful, thank you. I'm particularly interested in this business of diagnosis, dimensional versus categorical, and the reason is I have a patient who I thought was bipolar II for many years, depressed pretty much only, but high-functioning, Most recently, though, had a very serious manic, psychotic episode, which had not happened in 15 years, and so now I'm wondering, bipolar II, bipolar I, your thoughts about that? Well, this is quite interesting because, again, it's a complex disease, and I think that has to be considered more dimensional than categorical. But also, we need to consider the conventional, I mean, the conventional use of diagnosis. For instance, to me, the idea that a person starts with a depression, but it is actually a pseudo-depressive person because, I mean, at some point, it will become bipolar. I mean, to me, the person is depressed until he has depressions, and then it would be bipolar when he has, bipolar II when he has hypomania, and then maybe it will become bipolar I when he has mania. So we confound the idea that it's not something written somewhere, the diagnosis. I mean, it's a convention. I mean, we have to follow the rules. I mean, criterias are that you need to fulfill some criteria for a diagnosis. Up to that point, you fulfill those criteria, and you belong to that diagnosis. Even before depression, the person might have a panic disorder. So, but not it was a panic disorder that at some point will be, because the idea of becoming a bipolar person comes later, and unless the person doesn't start with a mania, you cannot really make a diagnosis of bipolar disorder before the appearance of hypomania or mania. Right, I mean, you, I mean, it's, I mean, it's actually, it's kind of rare, but I mean, it happens that a person could have, first, a unipolar depression, and then bipolar II, and then bipolar I, maybe with psychosis. I mean, it depends on many different factors. Just one brief. We'll take a final question from you, sir. Just one brief comment. My late colleague, Dr. Jan Fawcett and I practiced together, and the use of establishing a long-term relationship with our bipolar patients and major depressive patients was extremely important, one of the major issues, because these are gonna be lifelong issues, and if you don't establish a rapport that is ongoing, the brief response to medication will be brief. Very true. Access to treatment and support system, you know, those are very important. When we compare the ones who do well with the ones who don't, that is a common thread there for sure. Thanks for saying that. Well, thank you all for being here. Thank you. Thank you for being here today.

ketamine

treatment

depression

treatment-resistant depression

response rates

glutamatergic neurotransmission

neuroplasticity

suicidal ideation

infusions

protocol

off-label use

bipolar depression

psychosocial interventions